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Ma, Jin-Xia, Dan-Dan Xu, Shun-Yuan Lu, Qian-Lan Wang, Lu Zhang, Rui Guo, Ling-Yun Tang, et al. "Stk10 Deficiency in Mice Promotes Tumor Growth by Dysregulating the Tumor Microenvironment." Biology 11, no. 11 (November 15, 2022): 1668. http://dx.doi.org/10.3390/biology11111668.
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Serine-threonine kinase 10 (STK10) is a member of the STE20/p21-activated kinase (PAK) family and is predominantly expressed in immune organs. Our previous reports suggested that STK10 participates in the growth and metastasis of prostate cancer via in vitro and in vivo data. However, the correlation between STK10 and the tumor microenvironment (TME) remains unclear. In this study, we assessed the relationship between STK10 and the immune cells in the tumor microenvironment of prostate cancer through bioinformatic analysis, and investigated the role of Stk10 in tumor growth using an Stk10 knockout mouse model. The results showed that STK10 is significantly associated with the tumor-infiltrating immune cells including lymphocytes, neutrophils, macrophages and dendritic cells. The target deletion of host Stk10 results in increased tumor growth, due to decreased activated/effector cytotoxic T lymphocytes (CTLs) and increased vessel density in the TME. In conclusion, we demonstrate that host Stk10 is involved in the host anti-tumor response by modulating the activated tumor-infiltrated CTLs and angiogenesis.
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Long, Zhangbiao, Jichun Yang, Xinyao Liu, Min Ruan, Danchen Meng, Junling Zhuang, Zhenqi Huang, Jian Ge, and Bing Han. "STK10 Mutation Block Erythropoiesis in Acquired Pure Red Cell Aplasia Via Down-Regulated the Ribosome Biosynthesis." Blood 142, Supplement 1 (November 28, 2023): 3825. http://dx.doi.org/10.1182/blood-2023-189722.
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Background: Acquired pure red cell aplasia (PRCA) is anemia associated with the absence of erythroblasts and characterized by persistent and easy recurrence. However, the underline mechanisms of acquired PRCA remain obscure, and the role of gene mutation in the pathogenesis of acquired PRCA was not elucidated yet. Aims: To identify gene mutations in acquired PRCA patients and their possible effects on the origin of the disease. Methods: Blood and buccal genome DNA extracted from thirty newly diagnosed patients with acquired PRCA were detected with whole exome sequencing. The candidate genes with high frequency in acquired PRCA but the low frequency in 1000 normal genomes which may affect protein function were selected. The pGreen-CMV-puro system was employed to generate lentivirus expressing short hairpin RNAs to target the candidate genes, and stable transfected K562 cell lines with silenced candidate genes were constructed. The erythroid and megakaryocytic differentiation was evaluated for the transfected K562 cell lines either by benzidine staining hemoglobin and CD235a expression or CD41 expression on the cell surface. STK10 gene was selected which affects the erythropoiesis. The influence of the STK10 gene on the expression of p53 mRNA/ protein was also detected. The RNA sequencing in STK10 silenced K562 cells was performed and KEGG enrichment was analyzed. Next, ribosome RNA synthesis was detected, and ribosome proteins and p53 signaling pathway were also detected by western blotting. Results: Through whole exome sequencing in patients with acquired PRCA, we confirmed that STK10 gene mutation is common in acquired PRCA patients, the mRNA/protein expression of STK10 was reduced and p53 increased in the bone marrow of the patients in which the gene mutated. Furthermore, the silence of the STK10 gene through the lentiviral vector harboring short hairpin RNAs in K562 cells could inhibit the erythropoiesis after being induced by Hemin. Whereas, CD41 expression was similar in STK10 silenced K562 cells to control K562 cells after being inducted by phorbol 12-myristate 13-acetate. We performed RNA sequencing in STK10 silenced K562 cells. KEGG enrichment analysis of differentially expressed ribosome biosynthesis pathway and p53 signaling pathway was affected. 28S and 18S in ribosome RNA synthesis impaired in these STK10 silenced K562 cells through RNA electrophoresis. Further, through the western blotting test in STK10 silenced K562 cells, we found ribosome proteins expression down-regulated and p53, phospho-p53 and p21 expression up-regulated due to STK10 mutated. Conclusion: STK10 gene mutation is common in patients with acquired PRCA and causes the reduction of mRNAs and protein expression in the mutated patients. The underlying research revealed STK10 gene mutation could affect the ribosome biosynthesis pathway and down-regulated the ribosome protein level, contributing to the abnormal erythropoiesis. This research elucidated the pathogenesis of PRCA, which may provide evidence for precise diagnosis and exploring potential therapeutic targets in patients with acquired PRCA. Keywords: pure red cell aplasia, mutation, erythropoiesis, STK10, ribosome biosynthesis
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FUKUMURA, KAZUTAKA, YOSHIHIRO YAMASHITA, MASAHITO KAWAZU, EIRIN SAI, SHIN-ICHIRO FUJIWARA, NAOYA NAKAMURA, KENGO TAKEUCHI, et al. "STK10 missense mutations associated with anti-apoptotic function." Oncology Reports 30, no. 4 (July 9, 2013): 1542–48. http://dx.doi.org/10.3892/or.2013.2605.
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Zhang, Lu, Shun-Yuan Lu, Rui Guo, Jin-Xia Ma, Ling-Yun Tang, Yan Shen, Chun-Ling Shen, et al. "Knockout of STK10 promotes the migration and invasion of cervical cancer cells." Translational Cancer Research 9, no. 11 (November 2020): 7079–90. http://dx.doi.org/10.21037/tcr-20-1601.
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Walter, Sarah A., Richard E. Cutler, Ricardo Martinez, Mikhail Gishizky, and Ronald J. Hill. "Stk10, a New Member of the Polo-like Kinase Kinase Family Highly Expressed in Hematopoietic Tissue." Journal of Biological Chemistry 278, no. 20 (March 13, 2003): 18221–28. http://dx.doi.org/10.1074/jbc.m212556200.
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Asquith, Christopher R. M., Tuomo Laitinen, James M. Bennett, Carrow I. Wells, Jonathan M. Elkins, William J. Zuercher, Graham J. Tizzard, and Antti Poso. "Design and Analysis of the 4‐Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure‐Activity Relationships." ChemMedChem 15, no. 1 (November 26, 2019): 26–49. http://dx.doi.org/10.1002/cmdc.201900521.
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Kuramochi, Satomi, Yoichi Matsuda, Fujiko Kitamura, Mieko Okamoto, Hajime Karasuyama, and Hiromichi Yonekawa. "Molecular cloning of the human gene STK10 encoding lymphocyte-oriented kinase, and comparative chromosomal mapping of the human, mouse, and rat homologues." Immunogenetics 49, no. 5 (April 7, 1999): 369–75. http://dx.doi.org/10.1007/s002510050509.
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Asquith, Christopher R. M., Tuomo Laitinen, James M. Bennett, Carrow I. Wells, Jonathan M. Elkins, William J. Zuercher, Graham J. Tizzard, and Antti Poso. "Cover Feature: Design and Analysis of the 4‐Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure‐Activity Relationships (ChemMedChem 1/2020)." ChemMedChem 15, no. 1 (January 7, 2020): 2. http://dx.doi.org/10.1002/cmdc.201900691.
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Sugawara, Yo, Hideharu Hagiya, Yukihiro Akeda, Dan Takeuchi, Noriko Sakamoto, Yuki Matsumoto, Daisuke Motooka, Isao Nishi, Kazunori Tomono, and Shigeyuki Hamada. "Community spread and acquisition of clinically relevant Escherichia coli harbouring blaNDM among healthy Japanese residents of Yangon, Myanmar." Journal of Antimicrobial Chemotherapy 76, no. 6 (March 24, 2021): 1448–54. http://dx.doi.org/10.1093/jac/dkab070.
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Abstract Background Carbapenemase-producing Enterobacterales (CPE) are spreading in hospitals, environment and retail foods in Yangon, Myanmar. Objectives To investigate whether CPE colonize healthy individuals living in Yangon and whether clinical-related strains are spreading in the community. Methods CPE was isolated from faecal samples obtained from healthy Japanese residents of Yangon with no history of hospitalization. Isolates were subjected to WGS using short- and long-read sequencers and compared with those previously isolated in Yangon. Results Six Escherichia coli strains harbouring blaNDM-1 or blaNDM-5 belonging to five different STs—ST10, ST38, ST48, ST410 and ST8453—were isolated from 69 volunteers. The ST38 isolates were related to those previously isolated from retail food in Yangon. The ST410 and ST8453 isolates were highly related to previous Yangon isolates including those of clinical and food origins. Conclusions The analysis suggested the acquisition of blaNDM-positive E. coli, which are disseminating in a clinical setting and through retail foods, by healthy residents in Yangon.
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Kaouass, M., M. Audette, D. Ramotar, S. Verma, D. De Montigny, I. Gamache, K. Torossian, and R. Poulin. "The STK2 gene, which encodes a putative Ser/Thr protein kinase, is required for high-affinity spermidine transport in Saccharomyces cerevisiae." Molecular and Cellular Biology 17, no. 6 (June 1997): 2994–3004. http://dx.doi.org/10.1128/mcb.17.6.2994.
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Eukaryotic polyamine transport systems have not yet been characterized at the molecular level. We have used transposon mutagenesis to identify genes controlling polyamine transport in Saccharomyces cerevisiae. A haploid yeast strain was transformed with a genomic minitransposon- and lacZ-tagged library, and positive clones were selected for growth resistance to methylglyoxal bis(guanylhydrazone) (MGBG), a toxic polyamine analog. A 747-bp DNA fragment adjacent to the lacZ fusion gene rescued from one MGBG-resistant clone mapped to chromosome X within the coding region of a putative Ser/Thr protein kinase gene of previously unknown function (YJR059w, or STK2). A 304-amino-acid stretch comprising 11 of the 12 catalytic subdomains of Stk2p is approximately 83% homologous to the putative Pot1p/Kkt8p (Stk1p) protein kinase, a recently described activator of low-affinity spermine uptake in yeast. Saturable spermidine transport in stk2::lacZ mutants had an approximately fivefold-lower affinity and twofold-lower Vmax than in the parental strain. Transformation of stk2::lacZ cells with the STK2 gene cloned into a single-copy expression vector restored spermidine transport to wild-type levels. Single mutants lacking the catalytic kinase subdomains of STK1 exhibited normal parameters for the initial rate of spermidine transport but showed a time-dependent decrease in total polyamine accumulation and a low-level resistance to toxic polyamine analogs. Spermidine transport was repressed by prior incubation with exogenous spermidine. Exogenous polyamine deprivation also derepressed residual spermidine transport in stk2::lacZ mutants, but simultaneous disruption of STK1 and STK2 virtually abolished high-affinity spermidine transport under both repressed and derepressed conditions. On the other hand, putrescine uptake was also deficient in stk2::lacZ mutants but was not repressed by exogenous spermidine. Interestingly, stk2::lacZ mutants showed increased growth resistance to Li+ and Na+, suggesting a regulatory relationship between polyamine and monovalent inorganic cation transport. These results indicate that the putative STK2 Ser/Thr kinase gene is an essential determinant of high-affinity polyamine transport in yeast whereas its close homolog STK1 mostly affects a lower-affinity, low-capacity polyamine transport activity.
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Bange, Erin, Melina E. Marmarelis, Wei-Ting Hwang, Yu-Xiao Yang, Jeffrey C. Thompson, Jason Rosenbaum, Joshua M. Bauml, et al. "Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non–Small-Cell Lung Cancer." JCO Precision Oncology, no. 3 (December 2019): 1–11. http://dx.doi.org/10.1200/po.18.00326.
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PURPOSE The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non–small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations. METHODS We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). RESULTS From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/ KRAS, 18 had STK11/ TP53, and seven had STK11/ KRAS/ TP53. Patients with STK11/ KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/ TP53 (4.3 months; log-rank P = .043), and STK11/ KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/ KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/ TP53 (28.3 months; log-rank P < .001), and STK11/ KRAS/ TP53 (22 months; log-rank P = .025). CONCLUSION Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.
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Tanaka, Susumu, Yoshiko Honda, Misa Sawachika, Kensuke Futani, Namika Yoshida, and Tohru Kodama. "Degradation of STK16 via KCTD17 with Ubiquitin–Proteasome System in Relation to Sleep–Wake Cycle." Kinases and Phosphatases 1, no. 1 (December 22, 2022): 14–22. http://dx.doi.org/10.3390/kinasesphosphatases1010003.
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Serine/threonine-protein kinase 16 (STK16) is a novel member of the Numb-associated family of protein kinases with an atypical kinase domain. In this study, we aimed to investigate the involvement of STK16 in sleep–wake mechanisms. We confirmed the expression of Stk16 in the murine hypothalamus, the sleep–wake center, and found considerable changes in STK16 protein levels in the anterior hypothalamus during the light–dark cycle. We found that the coexistence of the potassium channel tetramerization domain containing 17 (KCTD17), an STK16 interactor, caused STK16 degradation. In contrast, the proteasome inhibitor MG132 inhibited the degradation of STK16. In addition, polyubiquitinated STK16 was observed, suggesting that KCTD17 acts as an adapter for E3 ligase to recognize STK16 as a substrate, leading to STK16 degradation via the ubiquitin–proteasome system. The vast changes in STK16 in the anterior hypothalamus, a mammalian sleep center, as well as the reported sleep abnormalities in the ubiquitin B knockout mice and the Drosophila with the inhibition of the KCTD17 homolog or its E3 ligase cullin-3, suggest that STK16 plays a major role in sleep–wake regulation.
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Klein, Alexandra, Daniela Flügel, and Thomas Kietzmann. "Transcriptional Regulation of Serine/Threonine Kinase-15 (STK15) Expression by Hypoxia and HIF-1." Molecular Biology of the Cell 19, no. 9 (September 2008): 3667–75. http://dx.doi.org/10.1091/mbc.e08-01-0042.
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The serine/threonine kinase-15 (STK15) acts as a cell cycle regulator being overexpressed in various tumors. One mechanism that could contribute to overexpression of STK15 is tumor hypoxia where hypoxia-inducible factor-1 (HIF-1) is a major regulator of transcription. Therefore, we analyzed whether hypoxia and HIF-1 could contribute to overexpression of STK15. We found that hypoxia increased STK15 expression and STK15 promoter activity in HepG2 tumor cells. Overexpression of HIF-1α induced STK15 gene transcription, whereas HIF-1α siRNA and overexpression of prolyl hydroxylase 2 (PHD-2), a negative regulator of HIF-1α, reversed this effect. In addition, site-directed mutagenesis experiments and chromatin immunoprecipitation revealed that from the three putative hypoxia responsive elements (HRE) within the STK15 promoter only HRE-2 was functional and bound HIF-1. Further, siRNA against STK15 inhibited proliferation of HepG2 cells induced by hypoxia. These results show that STK15 gene transcription can be regulated by hypoxia and HIF-1 via HRE-2 of the STK15 promoter. Thus, tumor hypoxia may trigger overexpression of STK15 observed in various tumors.
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Han, Yun, and Junyan Su. "The landscape of STK11 mutations and hotspots in Chinese patients with solid tumors." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e15112-e15112. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e15112.
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e15112 Background: STK11 is a tumor suppressor gene, and loss-of-function mutations are oncogenic, due to loss of AMPK regulation of mTOR and HIF-1-α. STK11 has been identified as a tumor suppressor in several types of cancers. Emerging evidence suggests that STK11 mutations may influence clinical outcome and response to immunotherapy in cancer. However, the genomic features of STK11 are obscured in Chinese solid tumors. In this study, we investigated the landscape of STK11 in Chinese patients with solid tumors. Methods: Next-generation targeted sequencing of major cancer-related 599 genes in a large cohort of 5420 Chinese solid tumors. Results: STK11 mutations were identified in 184 (3.39%, 184/5420) Chinese solid tumors patients. Although STK11 mutations are negligible in solid tumors, endometrial cancer patients (15.79%), esophagus and esophagogastric junction cancer (9.09%), ovarian cancer (4.92%), and lung cancer (4.92%) possess relatively high rates of STK11 mutation. However, STK11 alterations were not found in head and neck cancer, kidney cancer, and CNS tumor cases. A total of 194 mutation sites have been identified in STK11, including 43 pathogenic/ likely pathogenic mutations, the most prominent mutational hotspots are P281fs, D194Y, W308C, S216F, D53fs, and Y60, occupying almost 48.84% of all mutations in STK11. A total of 17 patients harbored copy number variations (CNV) of STK11 in Chinese solid tumors, mainly occurring in the neuroendocrine tumor, breast cancer, and gastric cancer. Conclusions: We found a unique genomic feature of STK11 in Chinese solid tumor patients. Our results show that STK11 may be a potential therapeutic target.
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Figueroa-González, Gabriela, José F. Carrillo-Hernández, Itzel Perez-Rodriguez, David Cantú de León, Alma D. Campos-Parra, Antonio D. Martínez-Gutiérrez, Jossimar Coronel-Hernández, et al. "Negative Regulation of Serine Threonine Kinase 11 (STK11) through miR-100 in Head and Neck Cancer." Genes 11, no. 9 (September 8, 2020): 1058. http://dx.doi.org/10.3390/genes11091058.
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Background: Serine Threonine Kinase 11 (STK11), also known as LKB1, is a tumor suppressor gene that regulates several biological processes such as apoptosis, energetic metabolism, proliferation, invasion, and migration. During malignant progression, different types of cancer inhibit STK11 function by mutation or epigenetic inactivation. In Head and Neck Cancer, it is unclear what mechanism is involved in decreasing STK11 levels. Thus, the present work aims to determine whether STK11 expression might be regulated through epigenetic or post-translational mechanisms. Methods: Expression levels and methylation status for STK11 were analyzed in 59 cases of head and neck cancer and 10 healthy tissue counterparts. Afterward, we sought to identify candidate miRNAs exerting post-transcriptional regulation of STK11. Then, we assessed a luciferase gene reporter assay to know if miRNAs directly target STK11 mRNA. The expression levels of the clinical significance of mir-100-3p, -5p, and STK11 in 495 HNC specimens obtained from the TCGA database were further analyzed. Finally, the Kaplan–Meier method was used to estimate the prognostic significance of the miRNAs for Overall Survival, and survival curves were compared through the log-rank test. Results: STK11 was under-expressed, and its promoter region was demethylated or partially methylated. miR-17-5p, miR-106a-5p, miR-100-3p, and miR-100-5p could be negative regulators of STK11. Our experimental data suggested evidence that miR-100-3p and -5p were over-expressed in analyzed tumor patient samples. Luciferase gene reporter assay experiments showed that miR-100-3p targets and down-regulates STK11 mRNA directly. With respect to overall survival, STK11 expression level was significant for predicting clinical outcomes. Conclusion: This is, to our knowledge, the first report of miR-100-3p targeting STK11 in HNC. Together, these findings may support the importance of regulation of STK11 through post-transcriptional regulation in HNC and the possible contribution to the carcinogenesis process in this neoplasia.
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Ahronian, Leanne G., Preksha Shahagadkar, Lauren Flynn, Lauren Grove, Shangtao Liu, Samuel R. Meier, Binzheng Shen, et al. "Abstract 5584: Experimental ‘loss-of function’ annotation of STK11 mutations with prognostic and therapeutic implications (TNG260mutationfinder.com)." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5584. http://dx.doi.org/10.1158/1538-7445.am2024-5584.
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Abstract Loss of function mutations in Serine Threonine Kinase 11 (STK11) occur in 15% of lung adenocarcinoma and have been shown to drive resistance to immune checkpoint blockade clinically, as well as in preclinical models. Though STK11 is commonly inactivated in human cancer with strong implications for treatment outcomes, few STK11 mutations identified from tumor samples have been functionally characterized. TNG260 is an inhibitor of CoREST that is currently being investigated in combination with pembrolizumab for the treatment of STK11-mutant cancer (NCT05887492). Patients are eligible for enrollment in the TNG260 phase 1/2 trial if their tumor contains a deleterious STK11 mutation. To begin classifying non-annotated variants, over 2,000 distinct mutations in the STK11 gene were identified from STK11 literature or public repositories of tumor sequencing data such as AACR Project GENIE and ClinVar. Where possible, loss-of-function annotations were captured from literature or predictive tools such as PolyPhen-2. However, many STK11 variants, particularly missense mutations, have never been functionally characterized. We developed a functional screening approach to characterize STK11 alterations using the lung adenocarcinoma cell line A549. A549 cells contain homozygous loss of STK11 via a truncation mutation at Q37, and re-expression of wild-type STK11 in these cells strongly impairs their growth in vitro and in vivo. We created a library of STK11 variant cDNAs, each containing a unique barcode. This library was expressed in A549, and cells were maintained in vitro or in vivo to allow for positive selection of STK11 loss-of-function variants and depletion of variants that behave like wild-type STK11. At the end of the screen, variants were quantified by NGS using each mutant cDNA’s unique barcode and compared to well-annotated controls. These data were assembled to generate TNG260mutationfinder.com – the first website to curate STK11 variants with functional annotations. Citation Format: Leanne G. Ahronian, Preksha Shahagadkar, Lauren Flynn, Lauren Grove, Shangtao Liu, Samuel R. Meier, Binzheng Shen, Hannah Stowe, Hsin-Jung Wu, Yi Yu, Andre Mignault, Iga Sienczylo, Heather DiBenedetto, Silvia Fenoglio, Teng. Experimental ‘loss-of function’ annotation of STK11 mutations with prognostic and therapeutic implications (TNG260mutationfinder.com) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5584.
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Eksioglu, Eria, Gabriela M. Wright, Trent R. Percy, Kenneth L. Wright, and W. Douglas Cress. "Abstract 4454: Loss of CX3CL1 expression mediates immune evasion in STK11 mutated lung adenocarcinomas." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4454. http://dx.doi.org/10.1158/1538-7445.am2023-4454.
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Abstract Immunotherapy has improved survival for many cancer patients, especially for immunogenic malignancies such as lung cancer. However, even in lung cancer, the response rate for anti-PD1 therapy (for example) does not exceed 20%. Thus, it is critical to identify mechanisms that block the response to immune checkpoint therapies. STK11 (also known as LKB1) is encoded by the serine threonine kinase 11 gene (STK11). Patients harboring tumors with STK11 mutations have reduced infiltrates of cytotoxic T-cells and clinical studies have shown that they respond poorly to anti-PD1 or anti-PDL-1 therapies regardless of PDL-1 status, which otherwise predicts benefit. Herein, we have used gene expression data from a cohort of 442 lung adenocarcinoma patients to identify CX3CL1 (fractalkine) as a gene silenced in STK11 mutant tumors with potential to be a key direct modulator of the immune system relevant to STK11 loss. To further explore this hypothesis, we have edited the STK11 gene in A549 cells back to wild type (STK11 corrected). As predicted, restoration of STK11 function resulted in modest expression of CX3CL1 as measured by Western blotting. Unexpectedly, exposure of STK11 corrected cells to human immune cells isolated from the blood of healthy donors resulted in a 5 to 10-fold increase in CX3CL1 suggesting interactive signaling between tumor and immune cells. Using transwell assays and STK11 corrected A549 cells we find that restoration of functional STK11 increases immune cell migration, adhesion and invasion in vitro. Finally, cytotoxicity assays demonstrate that STK11 corrected A549 cells are 3 to 5-fold more sensitive to immune cell killing. Taken together these results suggest the hypothesis that CX3CL1 loss mediates immune evasion in STK11 mutant lung adenocarcinomas. Future work will further explore the mechanisms underlying this pathway in preclinical models. Citation Format: Eria Eksioglu, Gabriela M. Wright, Trent R. Percy, Kenneth L. Wright, W. Douglas Cress. Loss of CX3CL1 expression mediates immune evasion in STK11 mutated lung adenocarcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4454.
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Iglesia, Michael, Moh'd M. Khushman, Kian-Huat Lim, Brian Andrew Van Tine, Jingxia Liu, Katrina Sophia Pedersen, Xiuli Liu, et al. "STK11 alterations as predictive biomarkers of resistance to immune checkpoint inhibitors in multiple cancers with mismatch repair gene alterations." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 2619. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.2619.
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2619 Background: STK11 is an important tumor suppressor gene that encodes for a serine-threonine kinase involved in a variety of metabolic functions. STK11 alterations are associated with an inert or cold tumor microenvironment in KRAS-mutant lung adenocarcinoma, and are a major driver of primary resistance to immune checkpoint inhibitors (ICIs). Here, we explored STK11 alterations as predictive biomarkers of resistance to ICIs in multiple solid tumors with mismatch repair (MMR) gene alterations. Methods: The cBioCancer Genomics Portal (cBioportal, http://www.cbioportal.org ) was used to obtain genomic data. The association between STK11 alterations and median overall survival (mOS) was explored in an ICI-treatment cohort comprising a total of 1572 evaluable patients. This cohort includes patients with cancers of the lung, colon, unknown primary, head and neck, gastroesophageal, bladder, skin (melanoma), brain, breast and kidney that had received at least one dose of ICI. These were then cross-referenced with patients who had MSK-IMPACT testing done in the context of routine clinical care. Kaplan-Meier survival curves were generated and compared using log-rank testing. Results: In the ICI-treated patients cohort (N = 1572), 96 patients (6.1%) had STK11 alterations. Patients with STK11 alterations had higher median tumor mutation burden (TMB) than patients without STK11 alterations (8.81 mut/Mb vs. 5.87 mut/Mb, p < 0.0001). Yet, they had worse mOS (7 m, 95% CI: 6-13 m vs. 20 m, 95% CI: 18-22 m, p < 0.001). MMR alterations (not including gene promoter methylation) were identified in 103 (6.6%) and co-occurrence of STK11 with MMR alterations was identified in 9 (0.6%) patients. Compared to patients without MMR or STK11 alterations (N = 1382), the mOS was better in patients with MMR alterations without STK11 alterations (N = 94) (59 m vs. 19 m, p = 0.0004) and trending for worse in patients with MMR and STK11 alterations (N = 9) (5 m vs. 19 m, p = 0.117). The mOS was better in patients with MMR alterations without STK11 alterations compared to patients with MMR and STK11 alterations (59 m vs 5 m, p = 0.016). Controlling for KRAS mutation status, a multivariable Cox regression model shows that besides MMR and STK11 alteration status (p = 0.0008), BRAF mutant status (p = 0.0001, HR 0.598; 95% CI, 0.459-0.779) was another biomarker associated with significantly better OS. Lung cancer diagnosis was associated with worse OS (p = 0.0016, HR 1.340; 95% CI, 1.117-1.607). Conclusions: In a large cohort of ICI-treated patients with multiple cancers, STK11 alterations were associated with worse mOS despite having higher TMB. MMR alterations were only predictive of response to ICIs in patients without STK11 alterations. Our findings suggest that STK11 alterations in patients with MMR alterations could potentially identify patients who are less likely to respond to ICIs but more data are needed.
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Naqash, Abdul Rafeh, Charalampos S. Floudas, Asaf Maoz, Joanne Xiu, Yasmine Baca, Jia Zeng, Chul Kim, et al. "STK11/TP53 co-mutated non-small cell lung cancer (NSCLC) to display a unique tumor microenvironment (TME) and metabolic profile." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9087. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9087.
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9087 Background: Recent data suggest inferior responses to immune checkpoint inhibitors (ICIs) in STK11-mt NSCLC. TP53 is a critical tumor suppressor gene regulating DNA repair by arresting cells in the G1 phase in response to critical double strand breaks. We hypothesized that accumulated DNA damage from mutations in the TP53 gene might increase immunogenicity and potentially enhance benefit of ICIs in STK11-mt NSCLC. Methods: A total of 16,896 NSCLC tumors submitted to Caris Life Sciences (Phoenix, AZ) for targeted NGS (DNA-Seq, 592 genes) were analyzed. A subset (N = 5034 tumors) had gene expression profiling (RNA-Seq, whole transcriptome). PD-L1 (TPS) was tested with 22c3 antibody (Dako). Exome-level neoantigen load for STK11-mt NSCLC was obtained from published TCGA Pan-immune analysis (Thorsson et al. 2018). Non-parametric tests were used for comparing differences in tumor mutational burden (TMB) and neoantigen load. Transcriptomic analysis included differential gene expression and hierarchical clustering. Tumor immune cell content was obtained from transcriptome using Microenvironment Cell Population-counter (MCP). Publicly available data from the POPLAR/OAK trials of atezolizumab in advanced NSCLC were used to model PFS and OS for STK11-mt with TP53-mt (n = 14) and without TP53-mt (n = 20). Results: Of 16,896 NSCLC samples, 12.6% had an STK11-mt with the proportions of TMB-high (≥10 Mut/Mb), PD-L1 ≥ 50% and MSI-high being 55.9%, 11.8%, and 0.72%, respectively. STK11-mt vs. STK11-wt NSCLC did not differ in median TMB (Caris:10 vs. 10 Mut/Mb; p > 0.1) or neoantigen load (TCGA: 154.5 vs. 165; p > 0.1). Median TMB (13 vs. 9 Mut/Mb; p < 0.001) and neoantigen load (263 vs. 134; p < 0.001) were higher in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt. MCP analysis showed higher CD8, NK-cell and lower myeloid dendritic cell infiltration in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01). Expression of MYC and HIF-α were increased in the STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01) along with higher expression (p < 0.01) of genes associated with both glycolysis ( HK2, LDHA, ALDOA) and glutamine metabolism ( GOT2, PPAT2). Hierarchical clustering of STK11-mt adenocarcinomas (n = 463) for STING pathway genes (CCL5, CXCL10, cGAS) identified a STING-high and a STING low cluster. The STING high cluster was significantly enriched in TP53-mt (48 vs. 32%; p < 0.01).In the OAK/POPLAR cohort, median OS (HR is 1.14, 95% CI 0.53 - 2.48); p > 0.1) and PFS (HR 1.88, 95% CI 0.89-3.97, p = 0.098) were not statistically different between STK11-mt/ TP53-mt vs. STK-mt/ TP53-wt. However, the 15-months PFS was 21% in the STK11-mt/ TP53-mt vs 0% in the STK11-mt/ TP53-wt. Conclusions: STK11-mt NSCLC with TP53-mt are associated with an immunologically active TME with metabolic reprogramming. These intrinsic properties could be exploited to improve outcomes to ICIs in combination with metabolically directed agents.
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Donnelly, Liam L., Tyler C. Hogan, Sean M. Lenahan, Gopika Nandagopal, Jenna G. Eaton, Meagan A. Lebeau, Cai L. McCann, et al. "Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers." Carcinogenesis 42, no. 12 (November 19, 2021): 1428–38. http://dx.doi.org/10.1093/carcin/bgab104.
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Abstract Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs.
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Robé, Caroline, Katrin Daehre, Roswitha Merle, Anika Friese, Sebastian Guenther, and Uwe Roesler. "Impact of different management measures on the colonization of broiler chickens with ESBL- and pAmpC- producing Escherichia coli in an experimental seeder-bird model." PLOS ONE 16, no. 1 (January 7, 2021): e0245224. http://dx.doi.org/10.1371/journal.pone.0245224.
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The colonization of broilers with extended-spectrum β-lactamase- (ESBL-) and plasmid-mediated AmpC β-lactamase- (pAmpC-) producing Enterobacteriaceae has been extensively studied. However, only limited data on intervention strategies to reduce the colonization throughout the fattening period are available. To investigate practically relevant management measures for their potential to reduce colonization, a recently published seeder-bird colonization model was used. Groups of 90 broilers (breed Ross 308) were housed in pens under conventional conditions (stocking of 39 kg/m2, no enrichment, water and feed ad libitum). Tested measures were investigated in separate trials and included (I) an increased amount of litter in the pen, (II) the reduction of stocking density to 25 kg/m2, and (III) the use of an alternative broiler breed (Rowan x Ranger). One-fifth of ESBL- and pAmpC- negative broilers (n = 18) per group were orally co-inoculated with two E. coli strains on the third day of the trial (seeder). One CTX-M-15-positive E. coli strain (ST410) and one CMY-2 and mcr-1-positive E. coli strain (ST10) were simultaneously administered in a dosage of 102 cfu. Colonization of all seeders and 28 non-inoculated broilers (sentinel) was assessed via cloacal swabs during the trials and a final necropsy at a target weight of two kilograms (= d 36 (control, I-II), d 47 (III)). None of the applied intervention measures reduced the colonization of the broilers with both the ESBL- and the pAmpC- producing E. coli strains. A strain-dependent reduction of colonization for the ESBL- producing E. coli strain of ST410 by 2 log units was apparent by the reduction of stocking density to 25 kg/m2. Consequently, the tested management measures had a negligible effect on the ESBL- and pAmpC- colonization of broilers. Therefore, intervention strategies should focus on the prevention of ESBL- and pAmpC- colonization, rather than an attempt to reduce an already existing colonization.
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Kaufman, Jacob, Dwight Hall Owen, Regan Michelle Memmott, Gregory Alan Otterson, Kai He, Carolyn J. Presley, Daniel Spakowicz, et al. "Novel STK11 differentiation phenotype classifier STK11-DPC: Immunosuppressive tumor microenvironment (TME) and response to immune checkpoint blockade (ICB) in STK11-deficient NSCLC." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 2626. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.2626.
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2626 Background: Loss of STK11 occurs in 20-25% of NSCLC and confers poor prognosis and resistance to ICB. STK11 loss affects lineage plasticity in murine models and differentiation phenotypes in patients. However, interactions between differentiation state, TME, and clinical outcomes are not well characterized. Methods: This is a retrospective and descriptive study across eight transcriptomic datasets of 2118 non-squamous NSCLC with 314 STK11 mutations, including 628 patients randomized to docetaxel or atezolizumab in the OAK and POPLAR clinical trials. STK11-DPC applies a validated gene signature to assess functional STK11 loss, then uses a rule-based classifier to define three differentiation lineages: “Neuroendocrine,” “TTF1-Low,” and TTF1-Positive.” TME is assessed by xCell immune deconvolution, and patient outcomes assessed by Cox proportional hazards regression models. Results: STK11-DPC significantly outperforms STK11 mutations in predicting decreased MHC-1, MHC-2, interferon-stimulated genes, and immune infiltration (P < 1e-8 for each). Each of the three differentiation groups has low immune infiltration compared to STK11 WT tumors, but we observe distinctive TME phenotypes corresponding to the Neuroendocrine and TTF1-Low groups. Neuroendocrine tumors have low expression of pro-inflammatory genes in the TNF/NFKB and JAK/STAT signaling pathways (P < 1e-10), while TTF1-Low tumors show hallmarks of increased inflammation, with higher PMN-MDSC, CD8 and NK signatures, but relative exclusion of dendritic cells (P < 1e-6 for each). These differences persist after controlling for KRAS, KEAP1, and TP53 mutations. Conversely, STK11-deficient tumors in WT-like or TTF1-Positive groups have TME more similar to STK11-WT tumors and show increased immune infiltration. STK11-DPC was prognostic when applied to OAK and POPLAR, with worse OS in Neuroendocrine (HR 1.6, P = 0.006) and TTF1-Low (HR 2.4, P = 5.8e-10) groups. Survival in both arms was equally poor in these groups. In contrast, STK11-deficient tumors with WT-Like or TTF1-Positive phenotypes had better OS with atezolizumab compared to docetaxel (HR 0.5, P = 0.03). Conclusions: STK11-DPC is highly predictive of immune exclusion and NSCLC patient outcomes. It identifies STK11-deficient subsets with increased immune infiltration and improved ICB response, and two putatively immune-resistant subgroups with markedly different TME phenotypes: Neuroendocrine tumors have an anti-inflammatory phenotype, while TTF1-Low tumors exhibit chronic inflammation. Performance of STK11-DPC as a predictive biomarker warrants further validation in additional patient cohorts, while the apparent TME differences suggest distinct and non-overlapping mechanisms of ICB resistance and may guide development of precision treatment strategies.
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Prior, Shannon, Logan Sands, Sean Lenahan, Hailey Sarausky, Melissa Scheiber, David Seward, and Paula Deming. "Abstract 1791: Metabolic rewiring promotes metastatic potential upon glutamine deprivation in STK11 null KRAS-driven lung adenocarcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1791. http://dx.doi.org/10.1158/1538-7445.am2024-1791.
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Abstract Lung adenocarcinoma (LUAD) with concurrent oncogenic KRAS and STK11 loss-of-function mutations define an aggressive subtype characterized, in part, by increased metastasis. Loss of STK11, a tumor suppressor and nutrient sensor, leads to dysregulation of many critical cellular processes, including metabolism. As such, STK11 null cancers are “glutamine addicted” to support proliferative properties and the tumor microenvironment therefore becomes glutamine depleted. We hypothesize that conditions of glutamine stress promote metastatic potential in STK11 null KRAS-driven LUAD due to metabolic rewiring. To test this hypothesis, we utilized a cell culture model of KRAS-driven LUAD cell lines and corresponding STK11 knockout cell lines (∆STK11). Parental and ∆STK11 cells underwent the Seahorse mitochondrial stress test in full and glutamine-deficient media to obtain parameters of mitochondrial respiration at baseline and under conditions reflective of the tumor microenvironment, respectively. At baseline, ∆STK11 cells had a hypermetabolic phenotype associated with enhanced glutamine utilization. Deprivation of glutamine resulted in decreased mitochondrial respiration along with a significant increase in live, detached ∆STK11 cells compared to the parental line. Upon further examination, the detached ∆STK11 cells maintained the ability to re-adhere and proliferate in full media while the detached parental cells did not. Additionally, expression of pro-survival, anti-apoptotic and EMT markers in ∆STK11 cells were increased upon glutamine deprivation. To determine the mechanism(s) underlying this pro-metastatic phenotype, we employed heavy nitrogen labeling which revealed an upregulation of the hexosamine biosynthetic pathway (HBP). The HBP is an offshoot of glycolysis that serves as a central hub to regulate many cancer fitness pathways via O-GlcNAcylation; the addition of a GlcNAc moiety to serine/threonine residues of target proteins. Further assessment of O-GlcNAcylation levels via western and far western blot analysis revealed that parental cells had decreasing HBP flux concordant with decreasing glutamine concentration while ∆STK11 cells, conversely, had enhanced HBP flux upon decreasing glutamine availability. These observations suggest ∆STK11 cells utilize the HBP as a protective shunt under decreased glutamine availability. We are currently characterizing the invasive potential and anchorage-independence of parental and ∆STK11 LUAD cells upon glutamine deprivation. Future studies aim to establish the impact of HBP perturbation, both genetically and pharmacologically, on the described measures of metastatic potential. Overall, this work reveals novel insight into the molecular mechanisms altered downstream of STK11 loss that link glutamine metabolism with metastatic properties in KRAS-driven LUAD. Citation Format: Shannon Prior, Logan Sands, Sean Lenahan, Hailey Sarausky, Melissa Scheiber, David Seward, Paula Deming. Metabolic rewiring promotes metastatic potential upon glutamine deprivation in STK11 null KRAS-driven lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1791.
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Nandagopal, Gopika, Sean Lenahan, Hannah Ross, Hailey Sarausky, David Seward, and Paula Deming. "Abstract 2751: Functional assessment of STK11 C-terminal domain variants." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2751. http://dx.doi.org/10.1158/1538-7445.am2024-2751.
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Abstract STK11 mutations in KRAS-driven lung adenocarcinomas (LUADs) are associated with aggressive tumor phenotypes characterized by increased risk of metastasis and lower overall and progression free survival. STK11 is a serine-threonine kinase that is comprised of an N-terminal domain containing a nuclear localization signal, a kinase domain, and a C-terminal domain (CTD). In LUAD, STK11 loss of function impacts many aspects of coordinated cell motility and promotes alterations characteristic of metastasis including cell polarity and adhesion. Both kinase activity and subcellular localization are important for STK11 tumor suppressor function. Our objective was to develop a reliable method to identify pathogenic STK11 mutations. Using archival data from the University of Vermont Medical Center, we identified 28 STK11 missense variants that had not yet been functionally characterized. We evaluated the functional impact of these variants on STK11 kinase activity through detection of autophosphorylation using an in-vitro kinase assay, as well as their ability to induce p53 activity through a luciferase reporter. Of the variants studied, 5 were CTD mutations. These variants retained kinase activity and the ability to bind STK11’s partners STRAD-alpha and MO25 in co-immunoprecipitation assays. Although the CTD of STK11 has no catalytic activity, it is thought to be integral for translocation to the cytoplasm where it can colocalize with actin and the cell membrane. STK11 dependent regulation of directional migration requires both proper localization to the actin cytoskeleton and kinase activity. Moreover, it has been reported that the C-terminal polybasic motif of STK11 (aa403-426), consisting of 3 Lysine and 5 Arginine residues is key for its localization and activation of AMPK at the plasma membrane. Therefore, when ascertaining functional status of STK11 in vivo, it is important to consider kinase independent STK11 functions. In LUAD cell lines, we show through immunofluorescent microscopy that expression of a truncated construct encoding STK11 with a CTD deletion results in nuclear sequestration. Additionally, point mutants in 3 of the polybasic motif residues (R409W, K416E and K423E) retain kinase activity and STRAD-alpha binding, but also lead to nuclear sequestration - highlighting the importance of a multipronged approach when assessing STK11 function. Future studies will assess the ability of these C-terminal domain mutants to phosphorylate cytoplasmic substrates, and their impact on cell migration and invasion. Additionally, we will utilize the TurboID proximity ligation system to assess the effect of C-terminal domain point mutations on binding partner accessibility. Citation Format: Gopika Nandagopal, Sean Lenahan, Hannah Ross, Hailey Sarausky, David Seward, Paula Deming. Functional assessment of STK11 C-terminal domain variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2751.
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Suzuki, Sora, Catrina Ting, Bojidar Kandar, Te-An Chen, Anm Nazmul Khan, Thejaswini Giridharan, Brahm Segal, and Edwin H. Yau. "Abstract 108: Tumor-derived complement C3 is overexpressed in STK11 mutant non-small cell lung cancer and contributes to an immunosuppressive tumor microenvironment in a syngeneic mouse model." Cancer Research 84, no. 6_Supplement (March 22, 2024): 108. http://dx.doi.org/10.1158/1538-7445.am2024-108.
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Abstract Mutations in STK11 that lead to loss of its protein LKB1 occur in 15-20% of non-squamous non-small cell lung cancer (NSCLC) and are frequently co-mutated with oncogenic KRAS mutations. KRAS and STK11 co-mutant NSCLC is associated with poor prognosis, low PD-L1 expression, low T-cell infiltration, and poor response to immune-checkpoint inhibitors (ICI). Loss of LKB1 leads to altered transcriptional programs with the activation of CREB-dependent gene transcription and changes in the tumor microenvironment including recruitment of suppressive myeloid cells. We used the syngeneic Kras mutant murine CMT167 tumor cell line that is wild-type for Tp53 and Stk11 and sensitive to ICI and generated isogeneic Stk11 knockout cell lines (CMT167-Stk11-KO) by CRISPR/Cas-9 deletion. Loss of Stk11 recapitulated LKB1-loss transcriptional signatures and rendered CMT167 tumors resistant to ICI. Single-cell RNA sequencing (10x) of implanted tumors demonstrated significantly less CD8 T-cells and increased neutrophils (PMN) in Stk11-KO versus Stk11-WT tumors. Analysis of differentially expressed genes in the tumor compartment identified increased expression of complement pathway genes including the central mediator C3 in CMT-167-Stk11-KO tumors. Examination of a well characterized clinical cohort of human KRAS-mutant NSCLC patient samples with and without STK11 mutation confirmed the increased expression of complement C3 in STK11-mutant tumors. Analysis of a human NSCLC cell line panel demonstrated that C3 expression was modulated by LKB1. Knockout of C3 in CMT167-Stk11-KO tumor resulted in dramatic inhibition of tumor growth and re-sensitized CMT167-Stk11-KO tumors to ICI treatment in WT mice. Using C3-/- knockout mice, this effect was determined to be reliant on tumor-derived C3 and dependent on adaptive immunity as no difference in growth of CMT167-Stk11-KO tumors occurred in nude mice or in WT mice after CD8 T-cell depletion. We then compared the transcriptome of Stk11-KO tumor cells with and without C3 deletion, and observed that C3 upregulates the expression of Cxcl1, Cxcl2 and Cxcl3 which mediate PMN recruitment and activation. Since these chemokines ligate Cxcr2, we asked whether Cxcr2 mediated tumor growth and ICI resistance in Stk11-KO tumors. While treatment with single-agent Cxcr2 inhibitor and anti-PD-1 therapy had no effect on tumor growth, the combination resulted in significant suppression of tumor growth in vivo. These results support a role for tumor-derived C3 suppressing CD8 T-cell immunity, potentially indirectly through recruitment of PMN or inducing PMN suppressor function. Our results also provide rationale for targeting tumor-derived complement and inhibiting Cxcr2 to enhance ICI efficacy as novel therapeutic approaches in patients with STK11-mutant NSCLC. Citation Format: Sora Suzuki, Catrina Ting, Bojidar Kandar, Te-An Chen, Anm Nazmul Khan, Thejaswini Giridharan, Brahm Segal, Edwin H. Yau. Tumor-derived complement C3 is overexpressed in STK11 mutant non-small cell lung cancer and contributes to an immunosuppressive tumor microenvironment in a syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 108.
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GERHOLD, G., M. H. SCHULZE, U. GROSS, and W. BOHNE. "Multilocus sequence typing and CTX-M characterization of ESBL-producing E. coli: a prospective single-centre study in Lower Saxony, Germany." Epidemiology and Infection 144, no. 15 (June 30, 2016): 3300–3304. http://dx.doi.org/10.1017/s0950268816001412.
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SUMMARYThe increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria is a serious threat for current healthcare settings. In this study we investigated the molecular epidemiology of ESBL-producing E. coli at the University Medical Center Göttingen in Lower Saxony, Germany. All E. coli isolates with an ESBL phenotype were collected during a 6-month period in 2014. Multilocus sequence typing and CTX-M characterization were performed on 160 isolates. Of the ESBL-producing isolates 95·6% were CTX-M positive. Compared to recent Germany-wide studies, we found CTX-M-1 to occur in higher frequency than CTX-M-15 (44·4% vs. 34·4%). CTX-M-14 and CTX-M-27 were detected at 9·4% and 5·0%, respectively. The globally dominant sequence type (ST) 131, which is often associated with CTX-M-15, occurred at a relatively low rate of 24%. Major non-ST131 sequence types were ST101 (5%), ST58 (5%), ST10 (4·4%), ST38 (4·4%), ST410 (3·8%) and ST453 (3·1%). Several of these major sequence types were previously shown to be associated with livestock farming. Together, our study indicates that E. coli lineage distribution in individual healthcare settings can significantly differ from average numbers obtained in nationwide studies.
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Li, Qingchu, Cuilin Li, Haoyun Li, Liu Zeng, Zhiqiang Kang, Yu Mao, Xinyue Tang, et al. "STK11 rs2075604 Polymorphism Is Associated with Metformin Efficacy in Chinese Type 2 Diabetes Mellitus." International Journal of Endocrinology 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/3402808.
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Metformin is a classical oral antidiabetic drug, often recommended to be the first-choice treatment of type 2 diabetes mellitus (T2DM). Based on the previous research on STK11 and diabetes, we aimed to investigate the distributive characteristic of STK11 rs2075604 polymorphism and the potential influence of STK11 rs2075604 polymorphism on metformin efficacy among Chinese T2DM patients. There was no significant difference between T2DM patients (G = 64.8%, T = 35.2%) and healthy subjects (G = 62.7%, T = 37.2%) in STK11 rs2075604 genotype and allele frequencies. After 12 weeks of treatment, 62 patients were defined as the responders and 32 patients as nonresponders according to the decrease of HbA1c level. And the GT + TT genotype in STK11 rs2075604 can decrease HbA1c level more significantly than the GG genotype. Furthermore, the allele frequency of T in the STK11 rs2075604 was higher in the responders than the nonresponders (43.55% versus 26.56%). The T allele in the STK11 rs2075604 had a 2.133 times great chance of responding to metformin treatment. In conclusion, this study suggested that the STK11 rs2075604 genetic polymorphism was significantly associated with metformin efficacy in Chinese T2DM patients and the carriers of the T allele may gain a better therapeutic metformin efficacy compared with the G allele. This trial is registered with clinical study registration number NCT03155087.
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Sun, Chongbo, Yvette Newbatt, Leon Douglas, Paul Workman, Wynne Aherne, and Spiros Linardopoulos. "High-Throughput Screening Assay for Identification of Small Molecule Inhibitors of Aurora2/STK15 Kinase." Journal of Biomolecular Screening 9, no. 5 (August 2004): 391–97. http://dx.doi.org/10.1177/1087057104264071.
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STK15/Aurora2 is a centrosome-associated serine/threonine kinase, the protein levels and kinase activity of which rise during G2 and mitosis. STK15 overexpression induces tumorigenesis and is amplified in various human cancers and tumor cell lines. Thus, STK15 represents an important therapeutic target for small molecule inhibitors that would disrupt its activity and block cell proliferation. The availability of a robust and selective small molecule inhibitor would also provide a useful tool for identification of the potential role of STK15 in cell cycle regulation and tumor development. The authors report the development of a novel, fast, simple microplate assay for STK15 activity suitable for high-throughput screening. In the assay, γ-33P-ATP and STK15 were incubated in a myelin basic protein (MBP)-coated FlashPlate® to generate a scintillation signal. The assay was reproducible, the signal-to-noise ratio was high (11) and the Z′ factor was 0.69. The assay was easily adapted to a robotic system for drug discovery programs targeting STK15. The authors also demonstrate that STK15 is regulated by phosphorylation and the N-amino terminal domain of the protein. Treatment with phosphatase inhibitors (okadaic acid) or deletion of the N-amino terminal domain results in a significant increase in the enzymatic activity.
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Pons-Tostivint, Elvire, Alexandre Lugat, Jean-François Fontenau, Marc Guillaume Denis, and Jaafar Bennouna. "STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact." Cells 10, no. 11 (November 11, 2021): 3129. http://dx.doi.org/10.3390/cells10113129.
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The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.
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Patel, Ayushi, Soumyadip Sahu, Ke Geng, Salman Punekar, Janaye Stephens, Jiehui Deng, Ting Chen, et al. "Abstract 3916: TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3916. http://dx.doi.org/10.1158/1538-7445.am2024-3916.
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Abstract Loss of function (LOF) of the serine-threonine kinase STK11/LKB1, which has been reported in ~15% of non-small cell lung cancer (NSCLC), drives resistance to immune checkpoint therapies such as PD1. In vivo CRISPR screens in tumor-bearing immune competent mice identified the Corepressor of Repressor Element 1 Silencing Transcription (CoREST) complex as a synthetic lethal immune evasion target for STK11- mutant tumors. Here, we demonstrate that TNG260, a small molecule drug specifically targeting the CoREST complex, can sensitize STK11 mutant lung cancers to anti-PD1 immunotherapy. Combination treatment with TNG260 and anti-PD1 arrested KRAS/STK11 mutant NSCLC tumor growth with no major toxicity observed, as confirmed in both allograft and genetically engineered mouse models (GEMMs) of STK11 mutant NSCLC. Further transcriptional analysis via bulk RNA-seq revealed that treatment of KRAS/STK11 mutant lung tumors with TNG260 promotes genes related to inflammatory responses and suppresses genes related to cell cycle and mitotic checkpoint(s). This phenotype was not observed in STK11 wildtype KRAS/P53 mutant lung tumors. Furthermore, combinational treatment of TNG260 with PD1 antibody showed increased macrophages, neutrophils and dendritic cells signatures in vivo. Our data suggests that epigenetic reprogramming via TNG260 sensitizes STK11 mutant NSCLC tumors to anti- PD1 treatment via targeting of the CoREST complex. This work identifies new vulnerabilities in STK11 LOF cancers that can be exploited therapeutically. TNG260 is currently being investigated in combination with pembrolizumab for the treatment of STK11-mutant cancer (NCT05887492), including NSCLC. Citation Format: Ayushi Patel, Soumyadip Sahu, Ke Geng, Salman Punekar, Janaye Stephens, Jiehui Deng, Ting Chen, Leanne Ahronian, Minjie Zhang, Jannik Andersen, Brian Haines, Kwok-Kin Wong. TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3916.
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Hong, Runyu, Wenke Liu, and David Fenyö. "Predicting and Visualizing STK11 Mutation in Lung Adenocarcinoma Histopathology Slides Using Deep Learning." BioMedInformatics 2, no. 1 (December 30, 2021): 101–5. http://dx.doi.org/10.3390/biomedinformatics2010006.
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Studies have shown that STK11 mutation plays a critical role in affecting the lung adenocarcinoma (LUAD) tumor immune environment. By training an Inception-Resnet-v2 deep convolutional neural network model, we were able to classify STK11-mutated and wild-type LUAD tumor histopathology images with a promising accuracy (per slide AUROC = 0.795). Dimensional reduction of the activation maps before the output layer of the test set images revealed that fewer immune cells were accumulated around cancer cells in STK11-mutation cases. Our study demonstrated that deep convolutional network model can automatically identify STK11 mutations based on histopathology slides and confirmed that the immune cell density was the main feature used by the model to distinguish STK11-mutated cases.
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Nourmohammadi, Bahareh, Joseph M. Amann, Rahul Shivahare, Qin Ma, Zihai Li, David P. Carbone, and Jacob Kaufman. "Abstract 5088: Evaluating TNF-receptor associated factor 2 (TRAF2) as a targetable driver of immune resistance in LKB1 deficient non-small cell lung cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5088. http://dx.doi.org/10.1158/1538-7445.am2024-5088.
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Abstract STK11 is a serine-threonine kinase and tumor suppressor lost in about 25% of NSCLC. It potently regulates a network of downstream effector kinases in the AMPK family, thereby exerting major effects on cell signaling, metabolic activity, and epigenetic patterning. Clinically loss of STK11 in NSCLC is associated with poor response to immune checkpoint blockade. Several mechanisms of immune resistance have been identified involving both tumor intrinsic pathways as well as changes in the immune microenvironment. Dysregulation of cellular inhibitor of apoptosis proteins, specifically cIAP1 has been identified as a specific resistance mechanism, which was shown to also influence the STING pathway in the context of STK11 loss. However, there is a gap in understanding how loss of STK11 influences cIAP1 signaling.We evaluated cIAP1, its TRAF family member binding partners, and downstream NF-kB and immune signaling using a multiomic approach. Using CPTAC multiomic data of 110 lung adenocarcinomas, we observe discordance between protein vs mRNA expression for cIAP1, which shows no significant association with STK11 loss in mRNA, but is significantly over-expressed at the protein level (P<1e-4). Conversely, we identify TRAF2 as the only TRAF member whose expression is increased in STK11-deficient NSCLC, with concordant increase in both mRNA (P<1e-8) and protein (P<1e-10). Further, on the protein level TRAF2 and cIAP1 levels were highly correlated (P<1e-12), strongly suggesting that TRAF2 is the proximal factor driving dysregulation of cIAP1 signaling in these tumors. We also observe a correlated pattern of phosphorylation sites within cIAP1, TRAF2, and other NF-kB signaling members that we putatively link to STK11 loss. We confirm that TRAF2 mRNA is consistently over-expressed in STK11 deficient NSCLC across multiple additional transcriptomic datasets together comprising >2000 tumors. Across this large dataset we observe that among STK11-deficient tumors, TRAF2 is anti-correlated with NF-kB signaling and immune infiltration signatures, a relationship that is strikingly absent among the STK11-WT subset. Using GEMM cell lines (KRAS, TP53, STK11 GEMM; Winslow lab, Stanford), we derived STK11 mutant vs WT isogenic pairs and performed T-cell co-culture experiments using ovalbumin antigen and OT-I CD8 T-cells. This showed that inhibition of cIAP1 using birinapant was synergistic to CD8 cytotoxicity, as previously known, but the synergy was much more pronounced in STK11 mutant vs STK11-WT context (Bliss index 38, P<1e-10). Together, these data demonstrate that the link between STK11-loss and cIAP1 dysregulation is likely through over-expression of TRAF2, and support the strategy of targeting TRAF2/cIAP1 to overcome immune resistance STK11-deficient NSCLC. Citation Format: Bahareh Nourmohammadi, Joseph M. Amann, Rahul Shivahare, Qin Ma, Zihai Li, David P. Carbone, Jacob Kaufman. Evaluating TNF-receptor associated factor 2 (TRAF2) as a targetable driver of immune resistance in LKB1 deficient non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5088.
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Seward, David Joseph, Sean Lenahan, Allison Racela, and Israel Odekunle. "Abstract 3026: STK11 negatively regulates NFKB signaling in KRAS-driven lung adenocarcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3026. http://dx.doi.org/10.1158/1538-7445.am2024-3026.
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Abstract In the US, more people die each year from lung cancer than breast, colorectal, and prostate cancers combined. Despite advances in lung cancer detection and treatment, the overall prognosis for patients remains poor. Patients whose lung tumors harbor druggable mutations often experience initial responses with targeted therapies, but acquisition of therapy resistance results in 5-year survival rates that have remained near ~20%. Immune check-point inhibitors (ICI) promise to improve outcomes in patients with lung cancer by targeting mechanisms of immune evasion. Drugs that disrupt PD-L1-mediated immune evasion, including pembrolizumab and nivolumab, have revolutionized treatment for some cancers. Unfortunately, only ~30% of lung adenocarcinomas (LUADs) respond to anti-PD-1 therapy and we cannot reliably identify this group prior to treatment. This underscores the need to discriminate which patients will respond to ICI therapies, while simultaneously highlighting the ~70% non-responder rate. To that end, recent clinical studies have linked anti-PD-1 therapy resistance with Serine/Threonine Kinase 11 (STK11) loss of function (LoF). STK11 operates in a heterotrimeric complex with the pseudo-kinase STRADα and the scaffolding protein MO25 where it regulates numerous intracellular signaling networks impacting metabolism, proliferation, transcription, and cell morphology. Why STK11 LoF correlates with anti-PD-1 resistance in the context of KRAS-driven LUAD remains unknown and represents a critical question in lung oncology. As an initial approach to understand this phenomenon, we knocked-out STK11 in multiple KRAS-driven, STK11-competent human LUAD cell lines and performed whole transcriptome analyses to identify STK11-loss-dependent differential gene expression profiles. We assert the transcriptional mediators downstream of STK11 governing the changes we report represent therapeutic targets whose antagonism may restore anti-PD-1 efficacy. Supporting this rationale, our data has identified STK11-loss-dependent activation of the NFκ-B transcriptional network. NFκB is a master transcription factor that regulates numerous cytokines, but whether and/or how STK11 directs NFκB activity remains largely unaddressed. We highlight NFκB activation as a potential mechanistic link between STK11 loss and tumor-intrinsic cytokine upregulation. We speculate that STK11 normally acts as a key player in the negative feedback loop limiting NFκB activity. When STK11 is lost, that activity continues unabated. In summary, we propose STK11 loss drives anti-PD-1 therapy resistance by generating an altered tumor immune microenvironment via constitutive activation of NFκB-mediated cytokine production. In future we intend to assess strategies for reversing anti-PD-1 therapy resistance via disruption of the NFκB transcriptional axis in KRAS-driven LUAD lacking STK11. Citation Format: David Joseph Seward, Sean Lenahan, Allison Racela, Israel Odekunle. STK11 negatively regulates NFKB signaling in KRAS-driven lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3026.
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Tavolaro, Simona, Sabina Chiaretti, Monica Messina, Francesca R. Mauro, Ilaria Del Giudice, Roberta Maggio, Emanuela M. Ghia, et al. "Gene Expression Profile of Protein Kinases Reveals a Distinctive Signature of Chronic Lymphocytic Leukemia (CLL) and Points to a Role of Second Generation Protein Kinase Inhibitors." Blood 108, no. 11 (November 16, 2006): 2794. http://dx.doi.org/10.1182/blood.v108.11.2794.2794.
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Abstract Background. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of relatively mature B cells and by a very variable clinical course. This clinical heterogeneity is sustained by different biologic parameters, such as the mutational status of the immunoglobulin variable genes (IgVH), CD38 and ZAP-70 expression. In order to investigate the potential role of protein kinase (PK) inhibitors in CLL, we evaluated the gene expression profile of 1324 probesets annotated as PK using the HGU133 Plus2.0 Affymetrix arrays. Methods. We evaluated 44 CLL and 137 acute lymphocytic leukemia (ALL) patients. Two additional sets of CLL (49 cases) were utilized to validate the results obtained. Probesets identified as PK genes were used for all the analyses, namely unsupervised clustering, Analysis of Variance (ANOVA) and t-test analysis. ANOVA was performed using a p-value of ≤0.001: further selection was performed retaining only those probesets whose mean expression level was ≥300 in at least one group and showed a fold change difference of ≥1.5 across all groups. Finally, to specifically identify genes differentially expressed between different subclasses of CLL, a t-test was applied: probesets were required to have a p-value ≤0.05 and a fold change>1.5. Results. Unsupervised analysis, performed on CLL samples and different ALL subgroups, highlighted in CLL a unique and very homogeneous pattern characterized by the overexpression of a large set of PK; these results were further confirmed by ANOVA. Moreover, we identified 16 PK genes that were highly expressed in all 3 CLL sets analyzed. These genes codify for proteins with tyrosine kinase activity (SYK, LYN, BLK, LCK, JAK1, CSK and FGR), serin-threonin kinase activity (PIM2, PFTK1, TLK1, MAP4K1, PDPK1, PRKCB1 and STK10) or both (GRK6 and WEE1). Some of the selected genes are members of important protein kinase families, involved in cellular signaling, such as Src kinases (SFK), MAPK and JAK kinase family. PK expression was also analyzed in different CLL subclasses, subdivided according to different prognostic factors; in particular, we compared IgVH mutated vs unmutated patients, CD38+ vs CD38- cases and, finally, ZAP-70+ vs ZAP-70- patients in the 3 experimental CLL sets. Comparison between IgVH mutated vs unmutated cases highlighted a differential expression of ZAP-70 in all the 3 sets analyzed. Contrariwise, no PK was associated with the other prognostic parameters. Thus, these analyses did not show a specific signature associated with the abovementioned biologic features, suggesting that PK overexpression is specific of the disease itself rather than of CLL subclasses. Conclusions. Our results show that CLL is characterized by a very peculiar PK signature and identify some potential molecular targets. Moreover, our findings indicate that a common mechanism of PK-mediated deregulation is operational in CLL cells, independently of other prognostic factors. Based on these pre-clinical data, we propose that second generation PK inhibitors may have a role in the management of all CLL patients.
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Wang, Junjun, Juanjuan Liu, Xinmiao Ji, and Xin Zhang. "Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity." International Journal of Molecular Sciences 20, no. 19 (September 30, 2019): 4852. http://dx.doi.org/10.3390/ijms20194852.
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STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.
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Hempel, Louisa, Laura Amanda Boos, Luis Fábregas-Ibáñez, Gabriele Gut, Marta Nowak, Martin Zoche, and Andreas Wicki. "Loss of heterozygosity (LOH) in KEAP1/STK11-mutated lung adenocarcinoma to characterize a new subgroup of hard-to-treat patients with unmet need in the real-world setting." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 8641. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.8641.
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8641 Background: Recent research suggests that loss of heterozygosity (LOH) in KEAP1/STK11 mutated lung adenocarcinoma (LUAD) may present a new immunological and biological aggressive subtype unresponsive to current standard of care treatment options. Currently, there is limited data on the clinical impact of LOH in KEAP1/STK11 co-alterations in real-world settings. Methods: From November 1st, 2021, to October 1st, 2023, patients with LUAD and mutations detected by FoundationOne CDx in any of the genes KEAP1, STK11, KRAS were enrolled in the study. Clinical data, including overall survival (OS), duration of response to different treatment lines (DOR), and real-world progression-free survival (rwPFS) according to the treatment lines, were retrospectively assessed in patients who had given informed general consent. Multivariate Cox regression models included patient characteristics, selected two-way interactions, OS, LOH, PD-L1 status and rwPFS for patients with STK11, KEAP1, KRAS mutations. Results: A total of 104 patients were included, 63 (60.6%) males with a median age of 64.4 years; [range: 38-90]). 23 (22.1%) patients with STK11/KEAP1/KRASmutations, 15 (14.4%) patients with KEAP1/LOH mutations, 10 (10.4%) patients with STK11/KRAS mutations and six (5.8%) patients with STK11/KEAP1. In the KEAP1/LOH mutated subgroup, median OS (mOS) was 14 months (ms), whereas in the subgroup with KEAP1/KRASmutations mOS was 13 ms. Across all groups mOS was 14 ms. Compared to Keynote 189 with a PFS of 8.8 ms, rwPFS for the first treatment line (rwPFS1) was shorter in patients with KEAP1/LOH status and KRAS/STK11 mutations at 3.5 ms and 3 ms respectively. Additionally, DOR and rwPFS for further treatment lines were analyzed according to PD-L1 and TMB status, as well as the treatment lines patients received. Conclusions: Patients with mutations on STK11/KEAP1/KRAS or with LOH presented an mOS inferior to what is currently expected from historic data for metastatic LUAD, with a worse prognosis and shorter rwPFS1 for the subgroup of K EAP1/LOH, KEAP1/KRAS and KRAS/STK11. Surprisingly, the percentage of patients carrying concurrent mutations of interest was much higher in the analyzed population than previously described, emphasizing the importance of broad NGS panel testing, including STK11 and KEAP1 mutations. Our findings based on real-world data indicate that in addition to the already known STK11/KEAP1/KRASconcomitant mutations, KEAP1/LOH mutations define a new subset of hard-to-treat genetic alterations. These patients represent a subgroup associated with primary therapy resistance, highlighting a new unmet need for tailored therapeutic strategies. Furthermore, our data emphasizes the benefit of upfront panel sequencing, including STK11/KEAP1 mutations and LOH, to identify at-need patients.
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Marin-Acevedo, Julian A. A., Justin Wang Shi, Yan Han, Mya Tran, Ahmad Karkash, Weston He, Misty Dawn Shields, and Nasser H. Hanna. "Outcomes in STK11-, KEAP1-, and KRAS-mutant lung squamous cell carcinoma (LSCC) with use of immune checkpoint inhibitors (ICIs)." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e20504-e20504. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e20504.
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e20504 Background: Studies have suggested that STK11, KEAP1, and KRAS mutations impact response to ICIs in individuals with lung adenocarcinoma. The effect of these mutations in LSCC is unknown. Methods: We conducted a retrospective analysis from January 1, 2018 through December 31, 2023 evaluating individuals seen in the Indiana University Health System with STK11, KEAP1, or KRAS-mutant advanced LSCC treated with ICI-based therapy. Demographic information and baseline PD-L1 levels were collected. Response to therapy was assessed using standardized real-world criteria. Progression-free survival (PFS) was calculated using the Kaplan-Meier method and compared using a log-rank test. Results: Thirty-one of 316 evaluable patients with LSCC had a mutation in KEAP1, STK11, or KRAS. Twenty-one of those individuals had advanced disease treated with ICIs. Nine of 21 had tumors harboring KEAP1 and/or STK11, 10 had tumors harboring KRAS, and 2 had KRAS + STK11-mutant tumors. The median age was 67 years, 71% (15/21) were male, 86% (18/21) were White, 83% (15/18) had PD-L1 levels ≥1%, and 81% (17/21) were evaluable for response including 11 treated with ICIs + chemotherapy and 6 who received ICIs alone. The overall response rate (ORR) was 65% with 5 individuals having progressive disease (PD), 1 with stable disease (SD), and 11 exhibiting partial response (PR). Those receiving ICIs + chemotherapy had an ORR of 73% (3 PD, 8 PR). The ORR was 50% (2 PD, 1 SD, 3 PR) in the cohort treated with ICIs alone. Among those with KEAP1 and/or STK11 mutations, the ORR was 43% (4 PD, 3 PR). The ORR was 88% for the KRAS-mutant cohort (1 SD, 7 PR) and 50% in the KRAS + STK11 subgroup (1 PD, 1PR). The median PFS was 6.4 months for the entire population, 6.0 months for those treated with ICIs + chemotherapy, and 8.1 months for those receiving ICIs alone. Although the cohort size was limited, individuals with KRAS mutations appeared to have improved PFS compared to those with STK11, KEAP1, or KRAS + STK11 mutations treated with ICI-based therapy (Table 1). Conclusions: STK11, KEAP1, and KRAS mutations impact response to ICIs in individuals with LSCC. There was a trend toward improved ORR and PFS in those with KRAS-mutant LSCC treated with ICI-based therapy compared to those with STK11, KEAP1, or KRAS + STK11-mutations. [Table: see text]
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Sen, Utsav, and Triparna Sen. "Abstract LB014: Targeting Stearoyl-coA desaturase (SCD) as a therapeutic strategy in STK11/KEAP1 co-mutant non-small cell lung cancer." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB014. http://dx.doi.org/10.1158/1538-7445.am2023-lb014.
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Abstract Introduction: Non-small cell lung cancer (NSCLC) is a highly prevalent subtype of lung cancer. Recent findings in the field have improved the clinical outcomes for only a subset of patients who are responsive to immunotherapy or have targetable oncogenic drivers. We have previously showed that concomitant loss of Serine/Threonine Kinase 11 (STK11) and Kelch-like ECH Associated Protein1 (KEAP1) detected in up to 10% NSCLC cases, dramatically enhances cell proliferation and invasion in vitro and in vivo. Bulk RNA sequencing identified upregulation of genes involved in ferroptosis, which is an iron dependent form of programmed cell death, in STK11/KEAP1 double mutant models, nominating ferroptosis as a potential vulnerability in these tumors. However, the mechanism of ferroptosis evasion in this subset in not well understood. Methods: We performed an in vitro CRISPR screen in STK11/KEAP1 co-mutant, single mutant and wild type cell lines. To further characterize the role of ferroptosis regulators in STK11/KEAP1 co-mutant setting, we performed phospho-kinase arrays and RNA sequencing in STK11/KEAP1 cell lines followed by validation through western blotting. Additionally, we performed gene expression analysis in patient derived xenografts (PDX) models treated with the SCD inhibitor to further characterize the mechanisms by which SCD inhibition has synthetic lethal effects in STK11/KEAP1 co-mutant background. Results: CRISPR/Cas9 based genetic screening identified stearoyl-CoA desaturase (SCD), a gene involved in ferroptosis protection, as a potential therapeutic target in the STK11/KEAP1 double mutant tumors. We further demonstrate that SCD overexpression protects STK11/KEAP1 co-mutant NSCLCs from undergoing ferroptosis. Pharmacological inhibition of SCD significantly reduced viability of STK11/KEAP1 co-mutant NSCLCs and made the co-mutant cells sensitive to ferroptosis induction. Phospho-kinase array showed downregulation of JAK-STAT and AKT signaling, in STK11/KEAP1 co-mutant NSCLCs as compared to both STK11 and KEAP1 single mutant isogenic conditions. The downregulation of these pathways was confirmed by gene expression profiling. To further understand the role of SCD in regulating ferroptosis we are studying the effect of concurrent loss of STK11 and KEAP1 on SCD on lipid oxidizing capacity and ferroptosis in a comprehensive panel of NSCLC cell lines and testing whether ferroptosis protection due to SCD overexpression leads to enhanced tumorigenesis in this co-mutant subtype of NSCLC in vivo and in vitro. Conclusions: Our study demonstrates the biological differences between STK11/KEAP1 co-mutant NSCLC as compared to the single mutants or wildtype counterparts in a KRAS mutation agnostic manner. In this study, we further establish SCD as a potential therapeutic strategy in STK11/KEAP1 co-mutant NSCLCs. We also show that SCD-mediated ferroptosis evasion is linked to multiple oncogenic signaling pathways which could be associated with ferroptosis. In summary we define a new therapeutic approach to STK11/KEAP1 co-mutant NSCLC to improve survival outcomes for patients diagnosed with this devastating disease. Citation Format: Utsav Sen, Triparna Sen. Targeting Stearoyl-coA desaturase (SCD) as a therapeutic strategy in STK11/KEAP1 co-mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB014.
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Hu, Jing, Shuang Li, Xiaozhi Sun, Zhuoqing Fang, Lina Wang, Feng Xiao, Min Shao, et al. "Stk40 deletion elevates c-JUN protein level and impairs mesoderm differentiation." Journal of Biological Chemistry 294, no. 25 (May 15, 2019): 9959–72. http://dx.doi.org/10.1074/jbc.ra119.007840.
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Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) toward the extraembryonic endoderm, and Stk40 knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological functions of STK40 in mesoderm differentiation remain elusive. Here, we report that Stk40 ablation impairs mesoderm differentiation both in vitro and in vivo. Mechanistically, STK40 interacts with both the E3 ubiquitin ligase mammalian constitutive photomorphogenesis protein 1 (COP1) and the transcriptional regulator proto-oncogene c-Jun (c-JUN), promoting c-JUN protein degradation. Consequently, Stk40 knockout leads to c-JUN protein accumulation, which, in turn, apparently suppresses WNT signaling activity and impairs the mesoderm differentiation process. Overall, this study reveals that STK40, together with COP1, represents a previously unknown regulatory axis that modulates the c-JUN protein level within an appropriate range during mesoderm differentiation from mESCs. Our findings provide critical insights into the molecular mechanisms regulating the c-JUN protein level and may have potential implications for managing cellular disorders arising from c-JUN dysfunction.
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Royer, Cole M., Lauren K. Bialek, Hailey M. Sarausky, Shannon M. Prior, Gopika Nandagopal, Paula B. Deming, David J. Seward, and Melissa N. Scheiber. "Abstract 2772: Mechanisms linking STK11 loss with metastatic potential in KRAS-mutated lung adenocarcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2772. http://dx.doi.org/10.1158/1538-7445.am2024-2772.
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Abstract Metastasis is one of the major determinants of worsened patient prognosis and occurs in roughly 50% of lung adenocarcinoma (LUAD) patients at the time of diagnosis. Late-stage diagnosis of LUAD often results in the accumulation of a wide range of mutations in tumor cells, with altered KRAS being the most frequently encountered oncogenic driver. Co-mutation of the tumor suppressor STK11 is also common and occurs in 10-15% of KRAS-driven LUAD. Retrospective patient studies have demonstrated that concurrent oncogenic KRAS and STK11 loss-of-function mutations are associated with metastatic disease, poorer patient survival, and inferior therapy response. The purpose of this study was to identify molecular mechanisms by which STK11 loss results in a greater metastatic potential in KRAS-driven LUAD in hopes of exploiting that knowledge to improve patient outcomes. For our studies, we utilized the KRAS-mutated, STK11-intact human LUAD cell line NCI-H2009. Both parental and ∆STK11 (generated by CRISPR/Cas9) H2009 cells were seeded in Transwell® inserts coated with fibronectin. As expected, H2009 ∆STK11 cells displayed a 1.6-fold increase in trans-well migration compared to the parental line (SEM 14393 ± 877.3 cells, n=6; p<0.0001). To assess the invasive properties of parental and ∆STK11 cells in a three-dimensional environment, spheroids generated by hanging drop culture were embedded in Matrigel and imaged by light microscopy at zero and 24-hours post-embedding. Analysis demonstrates a 2.4-fold increase in invasion in ∆STK11 cells compared to parental cells (SEM 0.03 ± 0.01 mm2, n=19-21; p<0.0001). Three-dimensional LUAD spheroids have been reported to more closely recapitulate in-vivo tumor transcriptomes compared to two-dimensional monolayer cultures. qRT-PCR analyses of our spheroids demonstrate that loss of STK11 promotes a significant increase in the expression of lung cancer stem cell markers CXCR4, NANOG, CD44, and OCT4 (n=3-6; p<0.002). These markers are known to support stem cell maintenance, chemoresistance, as well as metastatic potential, suggesting a mechanistic link between STK11 and their transcriptional regulation. To assess the impact of STK11 loss on early and late-stage metastasis in-vivo, we will use an embryonic zebrafish xenograft model. Zebrafish represent a tractable metastasis model due to the number of conserved human homologs - most notable being the CXCR4/CXCL12 axis which models cross-communication between zebrafish endothelium and cognate human tumor ligands. Current and future studies focus on investigating the role of STK11 in regulating stem cell markers; thereby identifying potentially novel therapeutic targets for STK11 and KRAS co-mutated LUAD patients. Citation Format: Cole M. Royer, Lauren K. Bialek, Hailey M. Sarausky, Shannon M. Prior, Gopika Nandagopal, Paula B. Deming, David J. Seward, Melissa N. Scheiber. Mechanisms linking STK11 loss with metastatic potential in KRAS-mutated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2772.
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Ma, Hongbo, Ailian Hei, Ji Zhou, Ellen He, Sven Skog, and Jin Li. "Serum thymidine kinase 1 protein concentration for predicting early progression and monitoring the response to TACE in hepatocellular carcinomas: a network meta-analysis." Future Science OA 7, no. 7 (August 2021): FSO717. http://dx.doi.org/10.2144/fsoa-2021-0016.
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Aim: A meta-analysis was conducted to evaluate the clinical significance of serum thymidine kinase 1 protein concentration (STK1p) in distinguishing between hepatocellular carcinomas (HCC) and non-HCC for predicting early progression and monitoring the response to transarterial chemoembolization in HCC. Material & methods: A total of 24 eligible studies were included, containing 1849 HCC patients and 1069 healthy subjects. Results: The STK1p level significantly increased from normal controls to benign/pre-HCC and HCC (p < 0.0001). STK1p also increased significantly in sub-malignant groups: control being the lowest, followed consecutively by hepatic hemangioma, hepatitis B virus infection and hepatic cirrhosis (p < 0.05). After 1 month of transarterial chemoembolization treatment, STK1p level declined significantly, by 44.4% (p < 0.0001). Conclusion: STK1p is a useful prognostic biomarker in HCC.
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Lazdun, Yelena, Lydia Greenlees, Song Wu, Nicholas Holoweckyj, Fernanda Pilataxi, Susana Hayes, Brandon Higgs, and Katie Streicher. "Abstract 5547: EGFR inhibition decreases immunosuppressive cytokines and reduces growth in STK11 mutant NSCLC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5547. http://dx.doi.org/10.1158/1538-7445.am2022-5547.
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Abstract Mutations in the tumor suppressor gene STK11 have been associated with innate resistance to immune checkpoint inhibitors in NSCLC. Although this resistance mechanism is not fully defined, previous work has suggested a role for increased infiltration of suppressive immune cells in the tumor microenvironment. We investigated the ability of various treatments to alter immunosuppression associated with STK11 mutations to inform future treatment strategies in NSCLC. Comparison of STK11 mt and wt cell lines revealed 10-1,000-fold increased levels of the immunosuppressive cytokines IL-6 and IL-8 in STK11 mt lines. STK11 mt lines were treated with inhibitors of clinically actionable pathways (MEKi, ERKi, or EGFRi at 0.001-10 uM) and evaluated for changes in cell growth and cytokine production. Treatment with EGFRi significantly decreased IL-6 and IL-8 (≥25 fold) and inhibited cell growth (2-3 fold decreased IC50) in STK11 mt lines, which is particularly interesting since STK11 mt lines are EGFR wt. Both MEKi and ERKi also reduced cytokine production (≤7 fold for MEKi, ≤2 fold for ERKi), but neither recapitulated the magnitude of the changes observed with EGFRi. Genomic changes associated with increased sensitivity of STK11 mt lines to EGFRi included down-regulation (≥ 1.5-fold) of genes involved in EGFR signaling (BTC), as well as neutrophil and Treg recruitment (CXCL8, PPRB, CXCL1, CCL20). These alterations were associated with a substantial reduction of infiltrating neutrophils in a tumor spheroid model using STK11 mt NSCLC lines treated with EGFRi compared to control (0.8% vs. 13.6%). The in vitro effects of EGFRi were confirmed in vivo in STK11 mt NSCLC PDX models. Treatment with 100mg/kg of EGFRi led to 30% tumor growth inhibition compared to vehicle control and a decrease (≥1.7 fold) in cytokines (IL-6, IL-8, CXCL1, CXCL5) involved in recruitment of suppressive immune cells by day 13. The effect of this modification in cytokine secretion was an observed decrease (2.2 fold) in the absolute count of mMDSCs in tumors from EGFRi treated mice compared to vehicle control at day 7. A decrease in inflammatory cytokines and MDSCs was also observed with a lower dose of 6.25mg/kg of EGFRi. Our results suggest that EGFRi decreases cytokines/chemokines responsible for recruiting and maintaining neutrophils and other immunosuppressive cells in the TME of STK11 mt NSCLC. This, combined with the reduced growth of STK11 mt cells, indicate that EGFRi may promote important changes in the TME that could overcome innate resistance to checkpoint inhibition. Citation Format: Yelena Lazdun, Lydia Greenlees, Song Wu, Nicholas Holoweckyj, Fernanda Pilataxi, Susana Hayes, Brandon Higgs, Katie Streicher. EGFR inhibition decreases immunosuppressive cytokines and reduces growth in STK11 mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5547.
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Nishimura, Sadaaki, Masakazu Yashiro, Tomohiro Sera, Yurie Yamamoto, Yukako Kushitani, Atsushi Sugimoto, Shuhei Kushiyama, et al. "Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells." Carcinogenesis 41, no. 11 (March 31, 2020): 1616–23. http://dx.doi.org/10.1093/carcin/bgaa031.
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Abstract Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. A reason for the poor prognosis of SGC is that the driver gene responsible for SGC has not been identified. To identify the characteristic driver gene of SGC, we examined the genomic landscape of six human SGC cell lines of OCUM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12 and OCUM-14, using multiplex gene panel testing by next-generation sequencing. In this study, the non-synonymous mutations of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) gene were detected in OCUM-12, OCUM-2M and OCUM-14 among the six SGC cell lines. Capillary sequencing analysis confirmed the non-sense or missense mutation of STK11/LKB1 in the three cell lines. Western blot analysis showed that LKB1 expression was decreased in OCUM-12 cells and OCUM-14 cells harboring STK11/LKB1 mutation. The mammalian target of rapamycin (mTOR) inhibitor significantly inhibited the proliferation of OCUM-12 and OCUM-14 cells. The correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were examined using 708 primary gastric carcinomas by immunochemical study. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth and frequent nodal involvement, in compared with the high STK11/LKB1 expression group. Collectively, our study demonstrated that STK11/LKB1 mutation might be responsible for the progression of SGC, and suggested that mTOR signaling by STK11/LKB1 mutation might be one of therapeutic targets for patients with SGC.
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Robbins, Helen L., Peter Fletcher, Joshua Savage, Manita Mehmi, Yvonne Summers, Alastair Greystoke, Noelle O’Rourke, et al. "Abstract A115: mTOR targeting in STK11 deficient Non-Small Cell Lung Cancer (NSCLC): final results, pre-clinical rationale and biomarker analysis of a phase II trial of the mTORC1/2 inhibitor vistusertib in STK11 deficient lung adenocarcinoma (NLMT B2)." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): A115. http://dx.doi.org/10.1158/1535-7163.targ-23-a115.
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Abstract Background: STK11 loss of function is common in lung adenocarcinoma (LUAD). STK11 deficient LUAD demonstrates mTOR activation, increased HIF-1a expression and GLUT1 up-regulation, resulting in increased glucose metabolism. STK11 loss often co-occurs with KRAS mutation. KRAS and STK11 co-mutations synergise to drive metabolic re-programming and heightened glucose dependency, reversible with mTORC1/mTORC2 inhibition. mTORC2 is a central node driving enhanced glycolysis independent of Raptor and HIF-1α. mTORC1/2 inhibition suppresses pS6K, p4EBP1, HIF1a and GLUT1 in STK11/KRAS double mutant NSCLC cells and suppresses growth in vivo. Vistusertib (AZD2014) is a selective mTORC1/2 inhibitor. We report the results of outcomes of LUAD patients with STK11 loss+/-KRAS mutation treated with vistusertib, the first study to investigate the impact of mTOR inhibition in STK11 deficient LUAD. Results: 19 patients (17 per-protocol) had STK11 loss without concomitant KRAS mutation (cohort B2S). 30 patients had STK11 loss with concomitant KRAS mutation (26 per-protocol) (cohort B2D). The confirmed objective response rate (95% credible interval) was 3.8% (0.1 – 18.5) for B2S, 9.8% (2.4 – 24.3) for B2D. Durable clinical benefit ((DCB), defined as no progression at 4th 6 weekly on treatment CT assessment) rate was 14.6% (3.6 – 34.7) for B2S, 24.4% (11.1 – 42.3) for B2D. Tumour growth inhibition (median % change from baseline (range)) in those with DCB was -18.5% (-48.0, 3.0) and in those with progression <3 months/death +10.5% (-6.0, 42.0). Median PFS was 2.29 months (1.47 – 3.85) for B2S, 2.77 months (1.91 – 4.22) for B2D. Median OS was 9.84 months (6.23 – 16.85) for B2S, 6.08 months (4.20 – 9.26) for B2D. Clinically achievable concentrations of vistusertib achieve dose-dependent inhibition of STK11 deficient LUAD cell line viability in vitro. In contrast, IC50 for everolimus (mTORC1-only inhibition) exceeds pharmacologically achievable doses in all tested STK11 deficient cell lines. Rebound FOXO and Akt phosphorylation is observed after 48 hours of vistusertib treatment, with parallel activation of ERK. Longitudinal ctDNA from B2S/B2D were analysed using the Illumina TSO500 ctDNA platform. Using conventional p<0.05 for significance, 2 genes were enriched at progression versus baseline: SMARCA4 (3/36 pre, 11/27 post, p=0.005) and FOXP1 (0/36 pre, 4/27 post, p=0.029). TRAF2 mutations were non-significantly enriched post-treatment (1/36 pre, 5/27 post, P = 0.076). Conclusions: Despite strong rationale for mTORC1/2 inhibition in STK11 deficient LUAD, activity of vistusertib is modest. Pre-clinical work suggests that STK11 mutant LUAD cell lines are not exempt from relief of feedback inhibition during prolonged mTORC1/2 inhibition, driving Akt and FOXO phosphorylation. Further, longitudinal ctDNA analysis suggests that vistusertib treatment may drive selection for SMARCA4 mutations, which appears to be a common mechanism of resistance to targeted therapies. HLR and PF contributed equally. LB and GM contributed equally. Citation Format: Helen L Robbins, Peter Fletcher, Joshua Savage, Manita Mehmi, Yvonne Summers, Alastair Greystoke, Noelle O’Rourke, Sanjay Popat, Pooja Jain, James Spicer, Judith Cave, Paul Shaw, David Gilligan, Danielle Power, Dean Fennel, Andrew D Beggs, Lucinda Billingham, Gary Middleton. mTOR targeting in STK11 deficient Non-Small Cell Lung Cancer (NSCLC): final results, pre-clinical rationale and biomarker analysis of a phase II trial of the mTORC1/2 inhibitor vistusertib in STK11 deficient lung adenocarcinoma (NLMT B2) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A115.
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Manolakos, Peter, and Linda D. Ward. "A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer." Journal of Personalized Medicine 13, no. 6 (June 18, 2023): 1010. http://dx.doi.org/10.3390/jpm13061010.
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The Kirsten rat sarcoma viral oncogene homolog (KRAS) and serine/threonine kinase 11 (STK11) co-mutations are associated with the diverse phenotypic and heterogeneous oncogenic subtypes in non-small cell lung cancer (NSCLC). Due to extensive mixed evidence, there needs to be a review of the recent KRAS and STK11 mutation literature to better understand the potential clinical applications of these genomic biomarkers in the current treatment landscape. This critical review highlights the clinical studies that have elucidated the potential prognostic and predictive implications of KRAS mutations, STK11 mutations, or KRAS/STK11 co-mutations when treating metastatic NSCLC across various types of treatments (e.g., immune checkpoint inhibitors [ICIs]). Overall, KRAS mutations are associated with poor prognoses and have been determined to be a valid but weak prognostic biomarker among patients diagnosed with NSCLC. KRAS mutations in NSCLC have shown mixed results as a predictive clinical biomarker for immune checkpoint inhibitor treatment. Overall, the studies in this review demonstrate that STK11 mutations are prognostic and show mixed results as predictive biomarkers for ICI therapy. However, KRAS/STK11 co-mutations may predict primary resistance to ICI. Prospective KRAS/STK11-biomarker-driven randomized trials are needed to assess the predictive effect of various treatments on the outcomes for patients with metastatic NSCLC, as the majority of the published KRAS analyses are retrospective and hypothesis-generating in nature.
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Uba, Richie, Luis E. Raez, Katerine Dumais, Frank Gentile, Herman W. Powery, Gelenis Calzadilla Domingo, Paola Izquierdo, and Brian Hunis. "Serine/threonine kinase 11 (STK11) mutations and immunotherapy resistance in patients with non-small cell lung cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15055-e15055. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15055.
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e15055 Background: There is immune evasion and resistance to checkpoint inhibitors (CPI). Programmed death-ligand 1 (PD-L1) and Tumor mutational burden (TMB) might help us predict response, but we have not yet validated biomarkers that can predict resistance. Mutations (mut) in STK11 can induce epigenetic changes that confer proliferative advantages to cancer cells and preliminary reports have suggested that they can confer resistance to CPI. We investigated the role of STK11 and KRAS mut as markers of poor response to CPI in patients (pts) with non-small cell lung cancer (NSCLC). Methods: Clinical outcomes of 127 pts with stage IIIB-IV NSCLC who were tested for KRAS and STK11 mut and received CPI were evaluated for progression free survival (PFS) and overall survival (OS). For statistical analysis log-rank tests were used to compare OS and PFS, chi-squared tests were used to compare 1-year survivals and proportions among different variables, and Kaplan-Meier survival curves were used to report OS and PFS. Results: Of the 127 pts: 31 had STK11 mut, 14 had STK11+KRAS mut (SKM group), and 10 pts were in the SKMP group (STK11+KRAS mut+PD-L1 (-)). Median age was 65y (27-88y). Males were 54% of the total and 30 pts (24%) were Hispanic (H). STK11 mut patients had an inferior PFS and OS as shown in table. Pts in SKM and SKMP groups had worse outcomes; however, not all the P values were significant. The difference in OS and 1-year OS were very impressive and significant when compared between the SKMP group (4m and 30%) and the wild type group (15m and 73%). There were no significant differences in clinical outcomes for H vs. non-H White pts. Conclusions: The presence of STK11 mut were associated with shorter OS/PFS in NSCLC pts treated with CPIs, proving its utility as a negative predictive marker. This can be enhanced combining STK11 and KRAS mut and possibly adding PD-L1 (-). These findings are consistent with recent studies that have reported STK11 mut as a genomic driver of primary resistance. Due to the small sample size further studies will be needed to validate these findings. [Table: see text]
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Nobili, Gaia, Gianfranco La Bella, Maria Grazia Basanisi, Annita Maria Damato, Rosa Coppola, Rachele Migliorelli, Valeria Rondinone, Pimlapas Leekitcharoenphon, Valeria Bortolaia, and Giovanna La Salandra. "Occurrence and Characterisation of Colistin-Resistant Escherichia coli in Raw Meat in Southern Italy in 2018–2020." Microorganisms 10, no. 9 (September 8, 2022): 1805. http://dx.doi.org/10.3390/microorganisms10091805.
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Colistin is a last-resort drug for the treatment of infections by carbapenem-resistant Enterobacteriaceae, and the emergence of colistin resistance poses a serious clinical challenge. The aim of this study was to investigate the occurrence of colistin-resistant Escherichia coli in retail meat in Southern Italy in 2018–2020. Of 570 samples, 147 contained E. coli. Two out of 147 (1.4%) E. coli showed a non-wild-type phenotype to colistin and harboured mcr-1. mcr-1 was also detected in a wild-type isolate, resulting in a 2% mcr prevalence. mcr-1-positive isolates originated from turkey meat collected in Apulia (n = 2) and Basilicata (n = 1). A whole-genome sequencing analysis confirmed mcr-1.2 and mcr-1.1 in two and one isolate, respectively. The strains were diverse, belonging to three multi-locus sequence types (ST354, ST410, SLV of ST10) and harbouring genes mediating resistance to antimicrobials in two, six and seven classes. mcr-1 was carried by IncX4 plasmids with high nucleotide similarity to IncX4 plasmids harbouring mcr-1.2 and mcr-1.1 in Enterobacterales from different sources and geographical regions. This is the first study reporting updates on E. coli non-wild-type to colistin from retail meat in Southern Italy, highlighting the importance of phenotypic and genotypic antimicrobial resistance surveillance to contain the dissemination of mcr among E. coli.
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Durani, Vidushi, Corrin A. Wohlhieter, Alvaro Quintanal-Villalonga, Triparna Sen, Parvathy Manoj, and Charles M. Rudin. "Abstract 3000: Ferroptosis evasion as a therapeutic strategy in STK11/KEAP1 co-mutant lung adenocarcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3000. http://dx.doi.org/10.1158/1538-7445.am2022-3000.
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Abstract Introduction Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, accounting for almost 50% of lung cancer cases. Comprehensive molecular characterization of LUAD tumors has identified actionable drivers and led to the development of targeted inhibitors that have substantially improved patient survival. Our team previously showed that concomitant mutational inactivation of Serine/Threonine Kinase 11 (STK11) and Kelch-like ECH Associated Protein1 (KEAP1), found in up to 10% of LUAD cases, enhances cell proliferation and invasion in vitro and in vivo. Bulk RNA sequencing identified upregulation of genes involved in ferroptosis, an iron-dependent form of programmed cell death, in STK11/KEAP1 double mutant models, nominating ferroptosis as a potential vulnerability in these tumors. Consistently, CRISPR/Cas9 based genetic screening identified stearoyl-CoA desaturase (SCD), a gene involved in ferroptosis protection, as a therapeutic target in the STK11/KEAP1 double mutant tumors. However, the mechanism of ferroptosis evasion in this subset in not well understood. Methods To further characterize the role of ferroptosis regulators in STK11/KEAP1 co-mutant setting, we performed phospho-kinase arrays and RNA sequencing in STK11/KEAP1 cell lines followed by validation through western blotting. We also performed gene expression analysis in patient derived xenografts (PDX) models treated with the SCD inhibitor to further characterize potential mechanisms by which SCD inhibition has synthetic lethal effects in STK11/KEAP1 co-mutant tumors. Results We demonstrate that SCD overexpression protects STK11/KEAP1 co-mutant LUADs from undergoing ferroptosis. Pharmacological inhibition of SCD significantly reduced viability of STK11/KEAP1 co-mutant LUADs and made the co-mutant cells sensitive to ferroptosis induction. Phospho-kinase arrays revealed decreased activation of the JAK-STAT and AKT signaling pathways in STK11/KEAP1-double KO LUADs models as compared to either STK11 or KEAP1 single mutant isogenic conditions, which was confirmed by RNA sequencing data showing downregulation of genes involved in these pathways specifically in the double knockout setting. Interestingly, SCD pharmacological inhibition by CVT-11127 reversed this phenotype and induced overexpression of genes involved in both pathways. Additionally, SCD genetic knock out in STK11/KEAP1-double KO LUADs models mimicked the effects observed after SCD pharmacological inhibition, supporting that these were derived from on-target drug action. Conclusions To summarize, these results suggest a potential interplay between STK11/KEAP1 function loss, ferroptosis protection, and the JAK-STAT and AKT oncogenic signaling pathways in LUAD. Further study of the role of these signaling pathways in ferroptosis may reveal mechanistic insight into the aggressive nature of these tumors. Citation Format: Vidushi Durani, Corrin A. Wohlhieter, Alvaro Quintanal-Villalonga, Triparna Sen, Parvathy Manoj, Charles M. Rudin. Ferroptosis evasion as a therapeutic strategy in STK11/KEAP1 co-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3000.
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Singh, Neeraj, and Smita Agrawal. "Abstract 2546: Identifying co-mutational signatures in STK11 mutated advanced non-small cell lung cancer (aNSCLC) patients that help overcome poor response to immune checkpoint inhibitors (ICI’s)." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2546. http://dx.doi.org/10.1158/1538-7445.am2024-2546.
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Abstract Background: ICIs, either alone or in combination with chemotherapy, have become the primary treatment options for aNSCLC patients without any targetable mutations. However, not all patients benefit similarly from these therapies even after selection based on the currently approved biomarker PD-L1 expression. Previous studies have shown that mutations in certain genes like STK11 and KEAP1 may predict non-response to these therapies. Mutations in STK11 occur in 25-30% of aNSCLC patients. We have used a real-world clinico-genomics dataset to investigate how this STK11+ aNSCLC patient population responds to ICIs in the context of other underlying co-mutations and whether some beneficial co-mutations may help patients overcome resistance due to their STK11 status. Methods: The ConcertAI Genome360TM NSCLC dataset (N=14193) was used in this retrospective study. aNSCLC patients who tested positive for STK11 mutations and received ICIs were considered (N=377). Based on their response to ICIs, the patients were divided into responder (N= 192) and non-responder (N=185) cohorts. Other genes with pathogenic mutations, fusions, and copy number changes were identified in both cohorts, and enrichment analysis was performed to identify co-mutations significantly enriched in one cohort vs the other. Once significant co-mutations were identified, pathway analysis was performed, taking into account the immune signaling network to help rationalise and validate the results. Results: One potential mechanism by which STK11 mutations influence the response to ICIs is through downregulation of the cGas-Sting pathway, which has been shown to play an important role in ICI response. Our co-mutational analysis also strongly supported this theory. We found that additional mutations that can nullify the effect of STK11 mutations on the cGas-Sting pathway led to a positive response (p=0.002) within the STK11+ cohort. Two such co-mutational signatures in responder patients identified were co-mutations in STK11/SMARCA4/TP53 (no KEAP1) (p-value = 0.003) and SKT11/KRAS/RBM10 (p-value = 0.04). Additionally, co-mutations in the DNA damage pathway genes (ATM, BRCA1, BRIP1, PALB2, STAG2) (p-value = 0.001) were also predictive of response to ICIs in the STK11+ cohort. Conclusion: By leveraging a real-world clinico-genomics dataset linking the tumor genomic profiles with patient response to ICIs, we have been able to perform a comprehensive co-mutational analysis of STK11+ aNSCLC patients to tease out the interplay of various biomarkers and signaling pathways that determine response to ICIs. Even though 25-30% aNSCLC patients are STK11+, we find that ~23% of these patients could still benefit from ICI treatment due to the presence of other co-mutations. Citation Format: Neeraj Singh, Smita Agrawal. Identifying co-mutational signatures in STK11 mutated advanced non-small cell lung cancer (aNSCLC) patients that help overcome poor response to immune checkpoint inhibitors (ICI’s) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2546.
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Berthelsen, Martin F., Siv L. Leknes, Maria Riedel, Mette A. Pedersen, Justin V. Joseph, Henrik Hager, Mikkel H. Vendelbo, and Martin K. Thomsen. "Comparative Analysis of Stk11/Lkb1 versus Pten Deficiency in Lung Adenocarcinoma Induced by CRISPR/Cas9." Cancers 13, no. 5 (February 26, 2021): 974. http://dx.doi.org/10.3390/cancers13050974.
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This study focused on STK11, PTEN, KRAS, and TP53, which are often found to be mutated in lung cancer. We compared Stk11 and Pten implication in lung cancer in combination with loss of Trp53 and gain of function of Kras in a CRISPR/Cas9 mouse model. Mice with loss of Stk11, Trp53, and KrasG12D mutation (SKT) reached human endpoint at around four months post-initiation. In comparison, mice with loss of Pten, Trp53, and KrasG12D mutation (PKT) survived six months or longer post-initiation. Pathological examination revealed an increase in proliferation in SKT deficient lung epithelia compared to PKT. This difference was independent of Pten loss, indicating that loss of Pten is dispensable for cell proliferation in lung adenocarcinoma. Furthermore, tumors with loss of Stk11, Trp53, and KrasG12D mutation had a significantly higher progression rate, monitored by PET/MRI scanning, compared to mice with loss of Pten, Trp53, and KrasG12D mutation, revealing that mutations in Stk11 are essential for adenocarcinoma progression. Overall, by using the CRISPR/Cas9 mouse model of lung adenocarcinoma, we showed that mutations in Stk11 are a key driver, whereas loss of Pten is dispensable for adenocarcinoma progression.