Journal articles on the topic 'PTPN11, tyrosine protein phosphatase non-receptor type 11'
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Sahu, Mahadev, Armiya Sultan, and Manas Ranjan Barik. "Molecular docking and high throughput screening of designed potent inhibitor to PTPN11 involved in Peptic Ulcer." South Asian Journal of Experimental Biology 6, no. 4 (December 23, 2016): 124–30. http://dx.doi.org/10.38150/sajeb.6(4).p124-130.
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In the current study we carried out computational drug designing and dock-ing studies on Tyrosine-protein phosphatase non-receptor type 11 (PTPN11). Scaffold selection was based on the functional properties of PTPN11. Leads were identified based on several physiochemical properties and we created our library with those new molecules that were generated based on Lipinski's rule of five. Further, we carried out high throughput screening on 21 molecules from scaffolds selected. Screening of molecules was based on the criterions such as, TOPKAT (toxicity analysis) and ADMET (absorption, distribution, metabolism, elimination) properties. Among the ligands de-signed, only one compound was identified to have premium interaction within the targeted domain. Pharmacophore was generated and analyzed for selected drug candidate. Our results suggest that O-(3-hydroxy-4-methoxyphenyl) S-methyl dithio dicarbonate is a potent drug molecule in terms of physiochemical and docking properties. In conclusion, the identified compound has great potential to inhibit tyrosine-protein phosphatase non-receptor type 11 (PTPN11).
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G, Bhusnure Omprakash. "In-silico exploration of piperine for invent proton pump and protein phosphatase non-receptor Inhibitors in gastric and peptic ulcer." Journal of medical pharmaceutical and allied sciences 11, no. 6 (December 31, 2022): 5334–38. http://dx.doi.org/10.55522/jmpas.v11i6.1865.
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Anti-ulcer medicines that inhibit the H/K-ATPase enzyme by covalently binding to a cysteine residue of proton pump inhibitors. Through the aforementioned processes, tyrosine-protein phosphatase non-receptor type 11 (PTPN11) causes aberrant mitogenic signals and elongated morphological alterations, as well as the growth and progression of peptic ulcer and gastric cancer.Piperine is an antioxidant derived from the Piper Longum herb. Molecular docking studies and virtual screening were used to investigate it as an H/K ATPase and PTPN11 inhibitor. The Molecular Docking examination was conducted using the Pyrx 0.8 version free database, while virtual screening was conducted using Biovia Discovery Studio software.H/K-ATPase and PTPN11 have substantial binding affinity of 7.5 and 8.6 kcal/mol, respectively, according to molecular docking investigations. Piperine's anti-ulcer efficacy appears to be aided by H/K-ATPase and PTPN11 binding
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Noordam, C., P. G. M. Peer, I. Francois, J. De Schepper, I. van den Burgt, and B. J. Otten. "Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11." European Journal of Endocrinology 159, no. 3 (September 2008): 203–8. http://dx.doi.org/10.1530/eje-08-0413.
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ContextNoonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce.ObjectiveTo determine the effect of long-term GH therapy in children with NS.DesignTwenty-nine children with NS were treated with GH until final height was reached.SettingHospital endocrinology departments.PatientsChildren with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene).InterventionsGH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months.Main outcome measureLinear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height.ResultsAt the start of treatment, median height SDS (H-SDS) was −2.8 (−4.1 to −1.8) and 0.0 (−1.4 to +1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0–10.3 years (median, 6.4), producing mean gains in H-SDS of +1.3 (+0.2 to +2.7) and +1.3 (−0.6 to +2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was +1.3, not different from the mean gain in the five children without a mutation in PTPN11+1.3 (P=0.98).ConclusionLong-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.
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Fobare, Sydney, Jessica Kohlschmidt, Hatice Gulcin Ozer, Krzysztof Mrózek, Deedra Nicolet, Alice S. Mims, Ramiro Garzon, et al. "Molecular, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia." Blood Advances 6, no. 5 (February 25, 2022): 1371–80. http://dx.doi.org/10.1182/bloodadvances.2021006242.
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Abstract Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations affect outcomes of patients treated with intensive chemotherapy. We studied 1725 patients newly diagnosed with AML (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (ie, FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes, providing a rationale to study the biology and treatment approaches in this molecular group. This trial was registered at www.clinicaltrials.gov as #NCT00048958 (CALGB 8461), #NCT00899223 (CALGB 9665), and #NCT00900224 (CALGB 20202).
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Idrees, Muhammad, Lianguang Xu, Seok-Hwan Song, Myeong-Don Joo, Kyeong-Lim Lee, Tahir Muhammad, Marwa El Sheikh, Tabinda Sidrat, and Il-Keun Kong. "PTPN11 (SHP2) Is Indispensable for Growth Factors and Cytokine Signal Transduction During Bovine Oocyte Maturation and Blastocyst Development." Cells 8, no. 10 (October 18, 2019): 1272. http://dx.doi.org/10.3390/cells8101272.
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This study was aimed to investigate the role of SHP2 (Src-homology-2-containing phosphotyrosine phosphatase) in intricate signaling networks invoked by bovine oocyte to achieve maturation and blastocyst development. PTPN11 (Protein Tyrosine Phosphatase, non-receptor type 11) encoding protein SHP2, a positive transducer of RTKs (Receptor Tyrosine Kinases) and cytokine receptors, can play a significant role in bovine oocyte maturation and embryo development, but this phenomenon has not yet been explored. Here, we used different growth factors, cytokines, selective activator, and a specific inhibitor of SHP2 to ascertain its role in bovine oocyte developmental stages in vitro. We found that SHP2 became activated by growth factors and cytokines treatment and was highly involved in the activation of oocyte maturation and embryo development pathways. Activation of SHP2 triggered MAPK (mitogen-activated protein kinases) and PI3K/AKT (Phosphoinositide 3-kinase/Protein kinase B) signaling cascades, which is not only important for GVBD (germinal vesical breakdown) induction but also for maternal mRNA translation. Inhibition of phosphatase activity of SHP2 with PHPS1 (Phenylhydrazonopyrazolone sulfonate 1) reduced oocytes maturation as well as bovine blastocyst ICM (inner cell mass) volume. Supplementation of LIF (Leukemia Inhibitory Factor) to embryos showed an unconventional direct relation between p-SHP2 and p-STAT3 (Signal transducer and activator of transcription 3) for blastocyst ICM development. Other than growth factors and cytokines, cisplatin was used to activate SHP2. Cisplatin activated SHP2 modulate growth factors effect and combine treatment significantly enhanced quality and rate of developed blastocysts.
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Li, Kang, Luobu Gesang, Zeng Dan, and Lamu Gusang. "Genome-Wide Transcriptional Analysis Reveals the Protection against Hypoxia-Induced Oxidative Injury in the Intestine of Tibetans via the Inhibition of GRB2/EGFR/PTPN11 Pathways." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/6967396.
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The molecular mechanisms for hypoxic environment causing the injury of intestinal mucosal barrier (IMB) are widely unknown. To address the issue, Han Chinese from 100 m altitude and Tibetans from high altitude (more than 3650 m) were recruited. Histological and transcriptome analyses were performed. The results showed intestinal villi were reduced and appeared irregular, and glandular epithelium was destroyed in the IMB of Tibetans when compared with Han Chinese. Transcriptome analysis revealed 2573 genes with altered expression. The levels of 1137 genes increased and 1436 genes decreased in Tibetans when compared with Han Chinese. Gene ontology (GO) analysis indicated most immunological responses were reduced in the IMB of Tibetans when compared with Han Chinese. Gene microarray showed that there were 25-, 22-, and 18-fold downregulation for growth factor receptor-bound protein 2 (GRB2), epidermal growth factor receptor (EGFR), and tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) in the IMB of Tibetans when compared with Han Chinese. The downregulation of EGFR, GRB2, and PTPN11 will reduce the production of reactive oxygen species and protect against oxidative stress-induced injury for intestine. Thus, the transcriptome analysis showed the protecting functions of IMB patients against hypoxia-induced oxidative injury in the intestine of Tibetans via affecting GRB2/EGFR/PTPN11 pathways.
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Binder, G., K. Neuer, M. B. Ranke, and N. E. Wittekindt. "PTPN11 Mutations Are Associated with Mild Growth Hormone Resistance in Individuals with Noonan Syndrome." Journal of Clinical Endocrinology & Metabolism 90, no. 9 (September 1, 2005): 5377–81. http://dx.doi.org/10.1210/jc.2005-0995.
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Abstract Context: Noonan syndrome is frequently associated with an unclear disturbance of GH secretion. Half the individuals with Noonan syndrome carry a heterozygous mutation of the nonreceptor-type protein tyrosine phosphatase, Src homology region 2-domain phosphatase-2 (SHP-2), encoded by PTPN11, which has a role in GH receptor signaling. Objective: The objective of this study was to compare GH secretion and IGF-I/IGF-binding protein-3 (IGFBP-3) levels of the SHP-2 mutation-positive (mut+ group) vs. mutation-negative individuals (mut− group). Design, Setting, and Patients: All children presenting to us with short stature plus at least three typical anomalies of Noonan syndrome or pulmonic stenosis during the last 5 yr (n = 29; 10 females and 19 males) were recruited. Auxological data, dysmorphic features, and cardiac morphology were documented. Hormone levels were measured by RIA. All coding exons of PTPN11 were sequenced after PCR amplification. Intervention: A prepubertal subgroup (n = 11) was treated with recombinant human GH (rhGH) to promote growth. Results: Sequencing yielded 11 different PTPN11 missense mutations in 16 of the 29 patients (55% mut+). Pulmonic stenosis (81 vs. 15%; P = 0.0007) and septal defects (63 vs. 15%; P = 0.02) were more frequently found in the mut+ group, whereas minor anomalies, cryptorchidism, and learning disabilities were as frequent in the mut+ group as in the mut− group. The mut+ group was younger at presentation (mean ± sd, 5.1 ± 2.7 vs. 10.3 ± 5.2 yr; P = 0.002), but not significantly shorter [−3.15 ± 0.92 vs. −3.01 ± 1.35 height sd score (SDS)]. IGF-I levels (−2.03 ± 0.69 vs. −1.13 ± 0.89 SDS; P = 0.005) and IGFBP-3 levels (−0.92 ± 1.26 vs. 0.40 ± 1.08 SDS; P = 0.006) were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation (P ≥ 0.075, not significant). The mean change in height SDS after 1 yr of rhGH therapy (0.043 mg/kg·d) was +0.66 ± 0.21 in the mut+ group (n = 8), but +1.26 ± 0.36 in the mut− group (n = 3; P = 0.007). Conclusions: Our data suggest that SHP-2 mutations in Noonan syndrome cause mild GH resistance by a postreceptor signaling defect, which seems to be partially compensated for by elevated GH secretion. This defect may contribute to the short stature phenotype in children with SHP-2 mutations and their relatively poor response to rhGH.
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Stevens, Brett M., Courtney L. Jones, Amanda Winters, James Dugan, Diana Abbott, Michael R. Savona, Stephen W. Fesik, Daniel A. Pollyea, and Craig T. Jordan. "PTPN11 Mutations Confer Unique Metabolic Properties and Increase Resistance to Venetoclax and Azacitidine in Acute Myelogenous Leukemia." Blood 132, Supplement 1 (November 29, 2018): 909. http://dx.doi.org/10.1182/blood-2018-99-119806.
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Abstract Previous studies have demonstrated the importance of energy metabolism as it relates to numerous aspects of leukemia stem cell (LSC) biology. Specifically, in acute myelogenous leukemia (AML), it has been shown that LSCs have a unique reliance on oxidative phosphorylation (OXPHOS), and that inhibition of B-cell lymphoma 2 (BCL-2) acts to down-regulate OXPHOS and eradicate LSCs in pre-clinical models. In the clinical setting, when BCL-2 inhibitor venetoclax is combined with azacitidine, high response rates (~80%) in elderly de novo AML patients have been observed (PMID: 29339097). Nonetheless, a significant portion of these patients ultimately experience disease progression. The mechanism of resistance and characteristics of these patients is poorly understood. Our preliminary data shows that the venetoclax + azacitidine (ven/aza) regimen targets LSCs through alteration of energy metabolism. Specifically, the regimen disrupts the TCA cycle leading to decreases in ATP production and inhibition of OXPHOS. This metabolic targeting is central to ven/aza efficacy and we hypothesize that resistance and progression of AML patients is due to compensatory mechanisms that restore sufficient levels of OXPHOS (PMID:3333149). Investigation of such mechanisms led us to explore the potential activity of MCL1. Previous studies have shown MCL1 can influence venetoclax resistance, however little is known about MCL1's role in metabolism, although a report in breast cancer cells suggests MCL1 modulates OXPHOS (PMID: 28978427). In leukemia, MCL1 expression has been shown to be partially upregulated through mutations in protein tyrosine phosphatase non- receptor type 11 (PTPN11), and PTPN11 mutations have been shown to increase LSC frequency. Thus, we hypothesized that PTPN11 mutations may confer resistance to venetoclax-based regimens at least partially by up-regulation of MCL1. To test this hypothesis, we investigated the relationship between PTPN11 mutations, MCL1, and the metabolic phenotype. In comparison to specimens with a wild type allele, LSCs isolated from PTPN11 mutant patient specimens showed increased levels of OXPHOS as well as glycolysis, amino acids, and fatty acids, suggesting an ability to utilize multiple energy sources for survival. PTPN11 mutant specimens also show decreased sensitivity to venetoclax, suggesting OXPHOS is not affected by venetoclax to the same degree as PTPN11 wild type specimens (fig. 1). Furthermore, when we introduced a mutated allele of PTPN11 into a primary AML specimen we observed increased oxidative phosphorylation and glycolysis, which correlated with decreased in vitro sensitivity to venetoclax (fig. 2). To test the potential role of MCL1 in PTPN11 mutant specimens, we employed a small molecule MCL-1 inhibitor. Metabolic analysis of specimens treated with the MCL-1 inhibitor showed decreased OXPHOS in PTPN11 mutant specimens (fig 3). Further, PTPN11 mutant specimens exhibit increased sensitivity to the MCL-1 inhibitor (fig. 4). To investigate a potential mechanistic link to clinical observations, we next examined 45 older, previously untreated AML patients from our institution who received ven/aza, both in the context of the multi-institutional study NCT02203773 (N=33) and with off-label use (N=12). Of 12 variables examined, only the presence of PTPN11 predicted shorter response duration (table 1). In addition, of the 9 patients who progressed ven/aza, 2 (22%) acquired PTPN11 mutations upon progression, further suggesting PTPN11 may represent a resistance mechanism to this regimen. Notably, PTPN11 is not preferentially detected in patients who progress after regimens other than ven/aza. In conclusion, AML containing PTPN11 mutations exhibit a unique energy metabolism profile. These specimens also appear to have increased sensitivity to MCL-1 inhibitors. The presence of PTPN11 mutations represents both a novel method for predicting response to ven/aza and a potential strategy for targeting patients who progress. We propose that addition of an MCL-1 inhibitor for treatment of AML patients bearing PTPN11 or related mutations may increase therapeutic responses. Disclosures Savona: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Consultancy. Fesik:Boehringer Ingelheim: Consultancy. Pollyea:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy.
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Shafaee, Maryam Nemati, Kristen Otte, Nicholas J. Neill, Kent C. Osborne, Thomas F. Westbrook, Susan Hilseneck, and Matthew J. Ellis. "Abstract OT2-28-01: A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704." Cancer Research 82, no. 4_Supplement (February 15, 2022): OT2–28–01—OT2–28–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-ot2-28-01.
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Abstract Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, disproportionally affecting African American and Hispanic patients, and germline BRCA1/2 mutation carriers. Prognosis of relapsed, metastatic disease is extremely poor and effective well-tolerated therapies are urgently needed. Our collaborators have discovered that TNBCs often lose feedback control of receptor tyrosine kinases (RTKs) including PDGFR and MET, locking these receptors in a chronically active state. These receptors share a common negative regulator called Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12). Baylor investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK inhibition. Sitravatinib is a spectrum selective RTK inhibitor that has shown strong antitumor activity in patient derived xenografts (PDXs) of TNBC with low levels of PTPN12. We have therefore designed a phase II, multi-institution, two cohort trials to evaluate the efficacy of sitravatinib in patients with metastatic TNBC (mTNBC). Methods: Patients with diagnosis of mTNBC who have received at least one line of chemotherapy +/- atezolizumab for advanced disease would be considered for enrollment. Patients would need to have tissue from metastatic site available for evaluation or agree to undergo biopsy if banked tumor tissue is not available. Sitravatinib at 100 mg daily, the recommended phase 2 dose for sitravatinib monotherapy, will be started at the initiation of the study and continued until progression or unacceptable toxicity. The study will employ a modified optimal Simon’s two stage design. Patients will be recruited into two cohorts: PTPN12 low or PTPN12 high/normal cohorts simultaneously and independently. Seven patients will be enrolled to each arm during the first stage. After the first stage, depending on the observed number of responses, the study will proceed to the 2nd stage. The primary endpoint is progression-free survival status at 24 weeks (PFS24). Current Trial status: The trial is funded by Mirati Therapeutics and opened to enrollment at Dan L Duncan Comprehensive Cancer Center (DLDCCC) clinics as of 6/8/21. Trial is due to open at UT Southwestern Dallas by 11/2021. The correlative science is funded by an institutional SPORE grant. Conclusion: This trial aims to show that sitravatinib is safe and to investigate whether it could be a treatment option in mTNBC. Citation Format: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis. A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-28-01.
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Kim, Jin Soo, Ok Ran Shin, Hyung Keun Kim, Young Seok Cho, Chang Hyeok An, Keun Woo Lim, and Sung Soo Kim. "Overexpression of Protein Phosphatase Non-receptor Type 11 (PTPN11) in Gastric Carcinomas." Digestive Diseases and Sciences 55, no. 6 (August 19, 2009): 1565–69. http://dx.doi.org/10.1007/s10620-009-0924-z.
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Gunawardana, Jay, Fong Chun Chan, Adele Telenius, Bruce W. Woolcock, Robert Kridel, King L. Tan, Susana Ben Neriah, et al. "Protein Tyrosine Phosphatase Type-1 (PTPN1) Is Frequently Mutated In Primary Mediastinal B Cell Lymphoma and Hodgkin Lymphoma." Blood 122, no. 21 (November 15, 2013): 242. http://dx.doi.org/10.1182/blood.v122.21.242.242.
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Abstract Introduction Hodgkin Lymphoma (HL) accounts for 11% of all lymphomas and despite being one of the most curable lymphomas, 20% of HL patients still ultimately die of their disease. Similarly, a proportion of cases of primary mediastinal B cell lymphoma (PMBCL) have refractory disease or early relapse and frequently fail second-line therapy. Development of more targeted therapeutic approaches is impeded by the lack of knowledge about the mutational landscape in the cancer genomes of these lymphomas. PTPN1 is a protein tyrosine phosphatase gene that encodes the protein, PTP1B. PTP1B dephosphorylates tyrosine residues on many activated kinases to maintain cellular homeostasis. As overactive receptor kinases are critical oncogenic events in cancer, we hypothesized that constitutively active Janus kinase-Signal transducer and activation of transcription (JAK-STAT) observed in HL and PMBCL are in part due to a mutated PTPN1 gene with an impaired functional ability to dephosphorylate this constitutive signaling pathway. Methods and samples Biopsies at the time of primary diagnosis were obtained for 49 PMBCL and 30 HL patients from the British Columbia Cancer Agency, Arizona Lymphoma Repository and the Hôpital Henri Mondor Pathology Department. DNA from PMBCL samples, microdissected Hodgkin Reed Sternberg (HRS) cells and 12 lymphoma-derived cell lines were extracted for PTPN1 exonic PCR amplification (nested PCR was used for HRS cell DNA) and Sanger sequencing. PTPN1 was silenced in a HL cell line (KMH2) by lentiviral transduction of a vector expressing shRNA and confirmed by quantitative real time (qRT) PCR. Wild type and mutant PTPN1 cDNA were cloned into the mammalian expression vector pcDNA 3.1 and expressed in HEK-293 cells. Protein expression of clinical samples, silenced and expressed cells were analyzed by immunohistochemistry and western blotting. Comparisons between groups were performed using two-sample student t tests. Results After exclusion of reported single nucleotide polymorphisms (SNPs) and silent mutations, 16 PTPN1 coding sequence mutations were found in our PMBCL cohort, corresponding to 14 mutations (29%) in clinical samples and 2 in PMBCL-dervied cell lines. Twelve additional mutations were discovered in our HL cohort, corresponding to 6 mutations (20%) in HRS cell samples and another 6 in HL-derived cell lines. In total, 14 (54%) missense, 4 (15%) frameshift, 3 (12%) single amino acid deletions, 4 (15%) nonsense mutations, and 1 (4%) promoter mutation were observed. Eight of these mutations were confirmed as somatic by sequencing of matched constitutional DNA. Silencing of PTPN1 resulted in hyperphosphorylation of JAK1, JAK2, STAT3, STAT5, STAT6 and up-regulation of the oncogenes, MYC and BCL6. Ectopic expression of nonsense and missense PTPN1 mutants in HEK-293 cells led to sustained phosphorylation of STAT6 in comparison to the empty vector control (densitometric values Q9* 0.5 vs. 1.0, R156* 0.7 vs. 1.0, M74L 0.4 vs. 1.0 and M282L 0.8 vs. 1.0). Furthermore, no phosphatase activity was observed for the nonsense mutants and moderate phosphatase activity for the missense mutants using a tyrosine phosphatase-specific substrate (fold change Q9* 2.0, R156* 1.9, M74L 46.7, M282L 46.0 and WT 58.3, compared to empty vector control). Immunohistochemical analysis showed that PTPN1 mutations correspond to decreased protein expression in PMBCL (p=0.03). Discussion PTPN1 is recurrently mutated in PMBCL and HL contributing to constitutive JAK-STAT signaling and oncogene dysregulation. These data suggest PTPN1 mutations as novel driver alterations in these lymphomas and might provide a novel, rational therapeutic target for treating HL and PMBCL patients. Disclosures: Savage: Eli-Lilly: Consultancy. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding.
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Elamin, Yasir, Sinead Toomey, Aoife Carr, Kenneth O'Byrne, Shereen Rafee, Kathy Gately, Oscar S. Breathnach, et al. "The role of protein tyrosine phosphatase non-receptor 11 (PTPN11) mutations in lung squamous cell carcinoma (SQCC)." Journal of Clinical Oncology 32, no. 15_suppl (May 20, 2014): e22174-e22174. http://dx.doi.org/10.1200/jco.2014.32.15_suppl.e22174.
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Becker, Helen M., Barbara Schnell, Joba M. Arikkat, Markus Schuppler, Martin J. Loessner, Michael Fried, Gerhard Rogler, and Michael Scharl. "Protein Tyrosine Phosphatase Non-Receptor Type 2 Regulates NLRP3 Inflammasome Activation." Gastroenterology 140, no. 5 (May 2011): S—633. http://dx.doi.org/10.1016/s0016-5085(11)62618-8.
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Spina, Valeria, Hossein Khiabanian, Alessio Bruscaggin, Monica Messina, Sara Monti, Antony B. Holmes, Sabina Chiaretti, et al. "The Coding Genome of Nodal Marginal Zone Lymphoma Reveals Recurrent Molecular Alterations of PTPRD and Other Jak/Stat Signaling Genes." Blood 124, no. 21 (December 6, 2014): 705. http://dx.doi.org/10.1182/blood.v124.21.705.705.
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Abstract Background. Nodal marginal zone lymphoma (NMZL) is one of the few B-cell tumors still remaining orphan of cancer gene lesions. By combining whole exome sequencing (WES), deep sequencing of tumor-related genes, high resolution SNP array and RNAseq, here we aim at characterizing the coding genome of NMZL and at disclosing the pathways that are molecularly deregulated in this lymphoma. Methods. The study was based on 35 NMZL (tumor representation >70%) with a diagnosis confirmed by: i) pathological revision of lymph node histology; and ii) lack of clinico-radiological evidence of extranodal or splenic disease either at diagnosis or during follow-up. Consistent with NMZL, the cases investigated: i) lacked CD5, CD10 and cyclin D1 expression, 7q deletion, t(11;14), t(14;18), t(11;18) and t(1;14) translocations; and ii) recurrently harbored +3 (14%), +12 (14%) and preferential usage of the IGHV4-34 gene (17%). WES (HiSeq 2500, Illumina; mean coverage per sample: 38x-114x) and high density SNP array (Cytoscan HD, Affymetrix) of tumor/normal DNA pairs from 18 discovery NMZL identified 557 non-synonymous somatic mutations (average: 30.9/case) affecting 504 genes and 61 copy number abnormalities (CNA) (average 3.4/case). To further characterize mutation recurrence, the 504 discovered genes were investigated in an independent validation panel of 17 NMZL by targeted sequencing of tumor/normal DNA pairs (MiSeq; target region: 1.6 Mb; mean coverage per sample: 171x-386x). The 17 validation NMZL were also assessed for CNA by high density SNP arrays. RNAseq of 11 discovery NMZL did not identify any recurrent gene fusion. Results. By compiling the results of WES and high resolution SNP array, 39 genes were recurrently affected in >3/35 (9%) NMZL by mutations (n=30 genes) or focal CNA (n=9 genes). Among these, MLL2 (34%), PTPRD (20%) and NOTCH2 (20%) were most frequently mutated. Overall, recurrently mutated genes pointed to the molecular deregulation of specific programs in NMZL, namely JAK/STAT, NOTCH, NF-κB and toll-like receptor (TLR) signaling, cell cycle, chromatin remodeling/transcriptional regulation and immune escape (Fig. 1A). JAK/STAT signaling was targeted by mutually exclusive lesions in 43% of NMZL, and the protein tyrosine phosphatase receptor delta (PTPRD) tumor suppressor was the most frequently affected gene of this system in 20% of NMZL (Fig. 1B-E). PTPRD inhibits JAK/STAT signaling through the dephosphorylation of active p-STAT3. PTPRD lesions in NMZL were represented by somatic mutations that truncated or modified the tyrosine phosphatase domain, as well as deletions of the entire gene locus, including focal and biallelic losses (Fig. 1B-C). Interrogation of institutional and public genomic datasets revealed that PTPRD mutations are specific for NMZL, being rare or absent in other mature B-cell tumors, including splenic marginal zone lymphoma (Fig. 1D). Other JAK/STAT signaling genes affected in NMZL were JAK2, CXCR4 (6%), PTPN2, JAK3, STAT2, SH2B3 and CUL3 (3%) (Fig. 1E). NF-kB signaling was altered in 54% of NMZL by lesions of TNFAIP3 (14%), BCL10, REL (11%), CARD11 (9%), TRAF3 and BIRC3 (6%). NOTCH signaling was targeted in 40% of NMZL by mutations that alternatively involved NOTCH2 (20%), SPEN (11%), RBPJL (6%), FBXW7, DTX1, ITCH and MAML2 (3%). TLR signaling was targeted in 17% of NMZL, including mutations of MYD88 (9%), IRAK1BP1, PELI2 and SEMP6 (3%). Several cell cycle genes were molecularly deregulated in 43% of NMZL, including CDKN2A, PARK2, PARKG (9%), CDC16, CDCA2 (6%), CCNA1, CCNT2, CDK5, CDK13, CDK20, BTG2, HECA and PLK2 (3%). Most (71%) NMZL harbored genetic lesions affecting epigenetic modifiers (MLL2: 34%; CREBBP: 9%; EP300: 6%; TRRAP: 6%), histones (20%) or transcriptional co-repressors (TBL1XR1: 14%; ARID1A: 14%; RCOR1: 11%; NCOR2: 9%, ARID1B: 9%). Finally, the TNFRSF14 and FAS genes, involved in T cell-mediated tumor surveillance, were disrupted by mutations and/or deletions in 17% and 14% NMZL, respectively. Conclusions. A number of actionable cellular programs are molecularly deregulated in NMZL, including JAK/STAT, NOTCH, NF-κB and TLR signaling, cell cycle and chromatin remodeling. PTPRD lesions are among the most recurrent alterations in NMZL and appear to be specific for this lymphoma type across mature B-cell tumors. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Scharl, Michael, Kacper A. Wojtal, Helen M. Becker, Anne Fischbeck, Joba M. Arikkat, Theresa Pesch, Silvia Kellermeier, et al. "Protein Tyrosine Phosphatase Non-Receptor Type 2 is a Regulator of Authophagosome Function." Gastroenterology 140, no. 5 (May 2011): S—172. http://dx.doi.org/10.1016/s0016-5085(11)60696-3.
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Elamin, Yasir, Sinead Toomey, Aoife Carr, Kathy Gately, Shereen Rafee, William Grogan, Patrick G. Morris, et al. "Protein tyrosine phosphatase non receptor 11 (PTPN11/Shp2) as a driver oncogene and a novel therapeutic target in non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 33, no. 15_suppl (May 20, 2015): 11077. http://dx.doi.org/10.1200/jco.2015.33.15_suppl.11077.
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Schubbert, Suzanne, Kenneth Lieuw, Sara L. Rowe, Connie M. Lee, XiaXin Li, Mignon Loh, D. Wade Clapp, and Kevin Shannon. "Functional Analysis of Leukemia-Associated PTPN11 Mutations in Primary Hematopoietic Cells." Blood 104, no. 11 (November 16, 2004): 2423. http://dx.doi.org/10.1182/blood.v104.11.2423.2423.
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Abstract The PTPN11 gene encodes SHP-2, a non-receptor protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21ras (Ras), Src family kinases, and other signaling molecules. Germ-line, missense mutations in PTPN11 account for approximately 50% of cases of the human developmental disorder Noonan Syndrome (NS). More recently, PTPN11 mutations have been identified in approximately 35% of children with juvenile myelomonocytic leukemia (JMML) without NS and have also been detected in other lymphoid and myeloid malignancies. Interestingly, almost all of these leukemia-associated mutations introduce amino acid substitutions within the N-SH2 domain of SHP-2 that are largely distinct from those found in NS. We have assessed the functional consequences of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Expression of an E76K mutant SHP-2 in murine fetal liver and bone marrow cells confers a hypersensitive pattern of colony-forming unit granulocyte-macrophage (CFU-GM) colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). Specifically, cells expressing E76K mutant SHP-2 display enhanced colony growth at low concentrations of growth factor compared to cells expressing wild-type (WT) SHP-2 protein. Mutant colonies are significantly larger with an abnormal, spreading morphology. E76K-expressing cells also form CFU-GM colonies in the absence of growth factor. The catalytic activity of the E76K mutant is required for aberrant colony growth as expressing the E76K mutation in the context of defective phosphatase activity (C463S) abolishes hypersensitive CFU-GM growth. Mutant E76K expression also enhances the growth of immature progenitor cells with high repopulating potential (HPP-CFC and LPP-CFC) in response to GM-CSF and IL-3 and perturbs erythroid progenitor colony growth. In addition, expressing the E76K mutation results in more pronounced growth factor hypersensitivity than another leukemia-associated SHP-2 mutation (D61Y), and both of these mutations confer a stronger hematopoietic phenotype than the common N308S substitution found in patients with NS.
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Huang, Hui, Zachary Waldon, Gordon Chan, Helen Zhu, Hanno Steen, Gen-Sheng Feng, Benjamin Neel, and Alan Cantor. "Tyrosine Phosphorylation of Runx1 In Megakaryocytes by Src Family Kinases." Blood 116, no. 21 (November 19, 2010): 742. http://dx.doi.org/10.1182/blood.v116.21.742.742.
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Abstract Abstract 742 Runx1 and its cofactor, CBF-beta, are the most frequent targets of chromosomal translocations in human leukemias. Point mutations in Runx-1 also occur in some cases of myelodysplastic syndrome and undifferentiated leukemia. During normal hematopoiesis, Runx1 is required for the ontogeny of all definitive hematopoietic stem cells and for the proper maturation of megakaryocytes (Mks) and lymphocytes. Despite these critical roles, the regulation of Runx1 activity via cell signaling pathways remains incompletely understood. Here, we report that Runx-1 is tyrosine phosphorylated in Mks. This occurs on multiple residues and is mediated by src-family tyrosine kinases (SFKs). Loss of Runx1 tyrosine phosphorylation correlates with phorbol ester induced differentiation of L8057 megakaryoblastic cells, suggesting a negative regulatory function. Consistent with this model, retroviral expression of a tyrosine non-phosphorylatable mutant Runx1 molecule increases primary murine fetal liver Mk maturation and Runx1 target gene expression to a greater extent than wild type Runx1. Moreover, treatment of wild type primary Mks with SFK inhibitors markedly enhances Mk maturation, as previously reported (Lannutti BJ, et al 2005 Blood;105:3875-3878). Treatment of L8057 cells with the pan-tyrosine phosphatase inhibitor Na3VO4, significantly increases Runx1 tyrosine phosphorylation levels, suggesting that tyrosine phosphorylation of Runx1 is dynamically regulated under steady-state conditions. Using a proteomic approach, we found that Runx1 physically interacts with the non-receptor tyrosine phosphatase SHP-2 (Ptpn11). We validated this interaction and showed that it occurs via direct interactions involving the Runx1 runt domain. ShRNA mediated knock down of SHP-2 in L8057 cells increases Runx1 tyrosine phosphorylation levels. Conditional knockout of SHP-2 in Mks using SHP-2fl/fl, PF4-Cre mice leads to reduced peripheral blood platelet counts and delayed platelet recovery following transient anti-GPIb antibody induced immune thrombocytopenia. Lastly, we show that treatment of TPA-induced L8057 cells with Na3VO4 markedly diminishes binding between Runx1 and the key Mk transcription factor GATA-1. Taken together, our data suggest that tyrosine phosphorylation of Runx1 via SFKs inhibits Runx1 function. Dephosphorylation, at least in part via SHP-2, relieves this inhibition and promotes Mk maturation. These effects are likely mediated through altered protein-protein interactions. Disclosures: No relevant conflicts of interest to declare.
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Oak, Shilpa, Cang Tran, Maria-Olivia Castillo, Shanthie Thamotharan, Manikkavasagar Thamotharan, and Sherin U. Devaskar. "Peroxisome proliferator-activated receptor-γ agonist improves skeletal muscle insulin signaling in the pregestational intrauterine growth-restricted rat offspring." American Journal of Physiology-Endocrinology and Metabolism 297, no. 2 (August 2009): E514—E524. http://dx.doi.org/10.1152/ajpendo.00008.2009.
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The effect of early intervention with a peroxisome proliferator-activated receptor-γ (PPARγ) agonist on skeletal muscle GLUT4 translocation and insulin signaling was examined in intrauterine (IUGR) and postnatal (PNGR) growth-restricted pregestational female rat offspring. Rosiglitazone [11 μmol/day provided from postnatal day (PN)21 to PN60] improved skeletal muscle insulin sensitivity and GLUT4 translocation in prenatal nutrient restriction [50% calories from embryonic day (e)11 to e21; IUGR] with (IUGR+PNGR) and without (IUGR) postnatal nutrient restriction (50% calories from PN1 to PN21; PNGR) similar to that of control (ad libitum feeds throughout; Con) ( n = 6 each). This was accomplished by diminished basal and improved insulin-responsive GLUT4 association with the plasma membrane in IUGR, IUGR+PNGR, and PNGR mimicking that in Con ( P < 0.005). While no change in p85-phosphatidylinositol 3-kinase (PI3-K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed, a decrease in protein tyrosine phosphatase 1B (PTP1B; P < 0.0002) and SH2-containing protein tyrosine phosphatase 2 (SHP2; P < 0.05) contributing to the rosiglitazone-induced insulin sensitivity was seen only in IUGR+PNGR. In contrast, an increase in phosphorylated 5′-adenosine monophosphate kinase (pAMPK; P < 0.04) and insulin responsiveness of phosphorylated phosphoinositide-dependent protein kinase-1 (pPDK1; P < 0.05), pAkt ( P < 0.01), and particularly pPKCζ ( P < 0.0001) and its corresponding enzyme activity ( P < 0.005) were observed in all four experimental groups. We conclude that early introduction of PPARγ agonist improved skeletal muscle activation of AMPK and insulin signaling, resulting in insulin-independent AMPK and insulin-responsive GLUT4 association with plasma membranes in IUGR, IUGR+PNGR, and PNGR adult offspring, similar to that of Con. These findings support a role for insulin sensitizers in preventing the subsequent development of gestational or type 2 diabetes mellitus in intrauterine and postnatal growth-restricted offspring.
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Jenkins, Chelsea, Samuel B. Luty, Julia E. Maxson, Christopher A. Eide, Bill H. Chang, and Jeffrey W. Tyner. "PTPN11 Mutations in JMML Confer Dasatinib Sensitivity in a TNK2-Dependent Manner." Blood 128, no. 22 (December 2, 2016): 3154. http://dx.doi.org/10.1182/blood.v128.22.3154.3154.
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Abstract Introduction: Juvenile myelomonocytic leukemia (JMML) is a rare disease characterized by an overproduction of granulocytes and monocytes, with cells displaying hypersensitivity to stimulation by the cytokine GM-CSF in culture. The only curative approach for JMML is allogeneic hematopoietic stem cell transplant, and disease recurrence is the leading cause of death in these patients, occurring within two years in 50% of patients. New therapeutic strategies are needed to improve treatment and survival. Methods: In order to better identify therapeutic strategies, our lab has developed ex vivo functional assays with small-molecule inhibitors and RNAi for the profiling of actionable targets in primary patient samples. In these assays, mononuclear cells from patient bone marrow or blood are cultured in the presence of small molecule inhibitor or RNAi libraries and cell viability is measured by colorimetric assay. To investigate targets identified in these assays, gene constructs are transfected into HEK293 T17 cells for immunoblots or transduced into mouse bone marrow cells for methylcellulose-based colony formation assays. Results: Mononuclear white blood cells from a patient with recurrent JMML were found to be sensitive to the multi-family kinase inhibitor dasatinib as well as siRNA targeting the dasatinib target tyrosine kinase non-receptor 2 (TNK2, also known as ACK1), suggesting an over-reliance on TNK2 for cell viability. TNK2 was recently demonstrated by our lab and others to regulate signaling downstream of signaling pathways including EGFR, ER, Src, and CSF3R. Based on the ex vivo functional data for this JMML specimen, the patient was placed on daily dasatinib and achieved marked improvement, which bridged the patient to an additional bone marrow transplant, resulting in disease-free survival for another year. This patient had a mutation in PTPN11 (also known as SHP2), which encodes a protein tyrosine phosphatase that is mutated in approximately 35% of JMML patients. PTPN11 is an auto-inhibited phosphatase that dephosphorylates targets in many signaling pathways including RAS-MAPK, with an overall positive effect on pathway activity and cellular proliferation. In JMML, mutations in residues of the N-terminal SH2 domain of PTPN11 result in a constitutively active form of the protein, which increases proliferation and cell survival and is linked to dysregulation of RAS/MAPK. Results of in vitro experiments demonstrate, for the first time, an interaction of TNK2 with mutant PTPN11. Co-expression of mutant-PTPN11 and TNK2 results in increased phospho-PTPN11 at two sites associated with activation of PTPN11 (Y542 and Y580), and co-immunoprecipitation experiments indicate direct interaction of TNK2 with PTPN11. These phosphorylation events coincide with significantly increased MEK/ERK signaling in the context of TNK2/mutant PTPN11 co-expression relative to expression of either gene alone. Expression of a TNK2 mutant harboring a loss-of-function mutation at a key activating residue (TNK2 Y284F) reduces PTPN11/MAPK activation, whereas expression of a gain-of-function, drug-resistant TNK2 gatekeeper mutant increases PTPN11/MAPK activation when compared to wild-type TNK2. Inhibition of TNK2 with either dasatinib or the TNK2-specific inhibitor AIM100 also reduces PTPN11/MAPK activation. Interestingly, phospho-TNK2 levels are significantly reduced in the presence of mutant-PTPN11, suggesting a feedback mechanism that has yet to be fully elucidated. Functional experiments suggest that mutant-PTPN11 and TNK2 work in a synergistic fashion to increase cell transformation and cytokine hypersensitivity. Mouse bone marrow cells transduced with both mutant PTPN11 and TNK2 have significantly more colonies in methylcellulose colony formation assays than with mutant- PTPN11 alone or with wild-type PTPN11 and TNK2. Treatment of cells in colony formation assays with either dasatinib or AIM100 inhibits colony formation, suggesting a dependence on TNK2 kinase activity for cell transformation. Conclusions: Taken together, the preliminary data suggest that PTPN11 mutations may be a functional marker for dasatinib sensitivity, and that the underlying mechanism for this sensitivity may be through the inhibition of TNK2 activity by dasatinib. Our aim is further validate the role of PTPN11 mutations as a marker for efficacy of dasatinib or other TNK2 inhibitors. Disclosures No relevant conflicts of interest to declare.
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Heinrich, Michael C., Andrea Haley, Patina Harell, Ajia Town, Troy Bainbridge, Marcus Schittenhelm, Laura McGreevey, and Rita Braziel. "Mutations of Oncogenes Involved in Signal Transduction Pathways Are Common in AML." Blood 104, no. 11 (November 16, 2004): 2575. http://dx.doi.org/10.1182/blood.v104.11.2575.2575.
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Abstract AML is the most common type of acute leukemia in adults. Patients typically respond to initial treatment with anthracycline and cytosine arabanoside-based induction chemotherapy, but most patients ultimately relapse and die of refractory disease. Despite advances in supportive care and stem cell transplantation, the overall cure rate in adult AML has not improved significantly in the last decade. The recent success of imatinib mesylate in treating CML has fueled enthusiasm for the further development of AML therapeutic approaches that selectively target aberrant intracellular signaling. To date, inhibition of signaling pathways that are dysregulated by tumor associated somatic mutations have produced the best clinical results. The goal of our study was to more precisely define the frequency and spectrum of mutations affecting receptor tyrosine kinases (FLT3, KIT, PDGFRA, PDGFRB), MAPK pathway (NRAS, KRAS, BRAF), PI3K pathway (PIK3CA), or multiple pathways (PTPN11 tyrosine phosphatase) in adult AML. We analyzed 109 cases of adult AML for genomic DNA abnormalities involving these pathways using a combination of D-HPLC and direct sequencing. In the case of PDGFRA, we performed RT-PCR and FISH to detect FIP1L1-PDGFRA translocations. At least one gain-of-function mutation was found in 53/109 cases (48.6%) (see table) We found mutations of FLT3, KIT, NRAS, KRAS, PTPN11 or BRAF in one or more cases in our series. In contrast, none of the 109 cases had identifiable mutations of PIK3CA, PDGFRA, or PDGFRB. While mutations of NRAS or KRAS were relatively common (19 cases), mutation of BRAF was rare (1/109). In general, mutations of KIT, FLT3, NRAS and KRAS appeared to be mutually exclusive with only 1 AML case having more than one mutation of these genes (1 case with NRAS and KRAS mutations). However, mutations of PTPN11 did not appear to follow this general rule as 5 of the 9 cases with PTPN11 mutations had additional gain-of-function mutation of either FLT3 (3 cases), NRAS (1 case), or both NRAS and KRAS (1 case). We are currently in the process of correlating these mutations with other clinical parameters. We conclude that mutations involving genes directly involved in signal transduction pathways can be found in approximately 50% of cases of adult AML. These mutations represent potential therapeutic targets for treatment with an appropriate small molecular inhibitor. We hypothesize that a more comprehensive kinome wide screen of AML cases would identify an even larger percentage of cases with somatic mutations involving signal transduction pathways. Mutations of PTPN11 have been reported in non-syndromic JMML and rarely in pediatric leukemia. However, the association of PTPN11 mutations in adult AML with mutations of FLT3 or NRAS has not previously been noted. Further studies are required to fully understand the cellular consequences of dysregulated PTPN11 in myeloid leukemogenesis. Our results may also be relevant to ongoing trials of FLT3 or farnesyl transferase inhibitors in AML, as patients with a co-existent PTPN11 mutation may not respond as well to monotherapy with these agents. Mutations of Signal Transduction Pathways in 109 Cases of Adult AML Mutations Number (%) None (wild-type for all genes) 56 (51.4%) FLT3 only 18 (16.5%) FLT3+PTPN11 3 (2.8%) NRAS only 11 (10.1%) NRAS+PTPN11 2 (1.8%) NRAS+KRAS 1 (0.9%) NRAS+KRAS+PTPN11 1 (0.9%) KRAS only 5 (4.6%) KIT only 6 (5.5%) PTPN11 only 4 (3.7%) BRAF only 1 (0.9%)
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Martin, Leenus, Roopal Patel, Jingchuan Zhang, Jennifer Yang, Robin Nevarez, Taylor Congdon, Les Brail, and Robert Shoemaker. "Abstract 2671: ERAS-601, a potent allosteric inhibitor of SHP2, demonstrates anti-tumor activity in RAS/MAPK-driven tumor models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2671. http://dx.doi.org/10.1158/1538-7445.am2022-2671.
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Abstract SHP2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. SHP2 transduces upstream receptor tyrosine kinase (RTK) signaling to the RAS/MAPK pathway via its phosphatase-mediated regulation of guanine nucleotide exchange factors (GEFs). The modulation of GEF activity impacts the rate at which KRAS cycles from the inactive GDP-bound state to the active GTP-bound state. ERAS-601 is a potent, selective small molecule allosteric inhibitor of SHP2. ERAS-601 potently inhibits the wild type SHP2 protein with a biochemical IC50 of 4.6 nM. ERAS-601 is a selective SHP2 inhibitor and demonstrates no appreciable inhibition against any off-target kinase or phosphatase across panels of 300 kinases and 12 phosphatases. ERAS-601 inhibits the loading of active GTP-bound oncogenic RAS and inhibits RAS/MAPK pathway signaling as measured by pERK1/2 inhibition and DUSP6 mRNA. ERAS-601 demonstrates anti-proliferative activity across a panel of human cancer cell line models with oncogenic alterations in the RAS/MAPK pathway. In a mouse in vivo study, ERAS-601 achieves substantial systemic exposure and demonstrates inhibition of ERK1/2 phosphorylation and DUSP6 mRNA levels in the NCI-H358 xenograft model. ERAS-601 also inhibits tumor growth in multiple RAS/MAPK-driven CDX and PDX models that harbor EGFR, KRAS, BRAF Class III, and NF1LOF mutations. ERAS-601 is a potent and selective allosteric SHP2 inhibitor that demonstrates anti-tumor activity in vitro and in vivo and is currently being studied as a monotherapy in an ongoing Phase 1 clinical study in patients with advanced or metastatic solid tumors (FLAGSHP-1, NCT04670679). Citation Format: Leenus Martin, Roopal Patel, Jingchuan Zhang, Jennifer Yang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker. ERAS-601, a potent allosteric inhibitor of SHP2, demonstrates anti-tumor activity in RAS/MAPK-driven tumor models [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 2671.
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Scharl, Michael, Kacper A. Wojtal, Helen M. Becker, Anne Fischbeck, Joba M. Arikkat, Theresa Pesch, Silvia Kellermeier, et al. "The Crohn's Disease Associated Variant of the Protein Tyrosine Phosphatase Non-Receptor Type 2 Gene Affects Cellular Responses to Invading Listeria Monocytogenes." Gastroenterology 140, no. 5 (May 2011): S—496. http://dx.doi.org/10.1016/s0016-5085(11)62052-0.
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Rao, A. Koneti, Robert Freishtat, Gauthami Jalagadugula, Anamika Singh, Guangfen Mao, Andrew Wiles, Peter Cheung, and Guenther Boden. "Alterations in Insulin-Signaling and Coagulation Pathways in Platelets During Hyperglycemia-Hyperinsulinemia." Blood 120, no. 21 (November 16, 2012): 633. http://dx.doi.org/10.1182/blood.v120.21.633.633.
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Abstract Abstract 633 Type 2 diabetes mellitus (T2DM) patients have increased incidence of acute vascular events, due in part to a prothrombotic/proinflammatory state with elevated plasma coagulation factors and enhanced platelet responsiveness. The hallmarks of T2DM, hyperglycemia (HG) and hyperinsulinemia (HI), are independent risk factors for mortality but their contributions to the prothrombotic mechanisms are unclear. Our prior studies in healthy non-diabetic subjects using infusion clamps showed that selective HI and HG, and more so the combination of HI+HG, increased circulating membrane-bound tissue factor-procoagulant activity (TF-PCA), plasma coagulation factor (F) VIII, and markers of thrombin generation. In addition, HI+HG induced platelet and monocyte activation and upregulated monocyte TF. In T2DM and type 1 DM patients, TF-PCA and FVII were elevated under basal conditions. To understand mechanisms underlying these prothrombotic changes in platelets and monocytes, we performed expression profiling of leukocyte-depleted platelets and monocytes before and after 24 h of HG+HI clamping in a healthy non-diabetic subject using U133 Plus 2.0 GeneChips (Affymetrix, Santa Clara, CA). Glucose was maintained ∼200 mg/dl by glucose infusion, which elevates endogenous insulin levels to induce HI. Profiling data was analyzed in Genomics Suite™ (Partek Inc.) to detect differentially expressed mRNAs. We generated a list of time-dependent differential mRNA expression (24 h fold change ≥2) common to both platelets and monocytes. Identification of biological pathways in which these genes may be critical players was determined in Ingenuity Pathways Analysis software. In particular, the insulin receptor signaling and coagulation canonical pathways were highly altered for both platelets and monocytes. A preliminary group of up or downregulated genes was selected from these for qRT-PCR confirmation (Table). For additional validity, the 24 h platelet sample was compared to the 0 h sample and 4 normal controls. Notably, 8 out of the 9 selected transcripts were confirmed in platelets and/or monocytes (Table, asterisks). In platelets, these include ↑GSK3B, ↓STXBP4 (Synip), ↑PTPN11 (platelet phosphatase SHP2) in insulin signaling, and ↑F3 (tissue-factor) and ↑TFPI on the coagulation side. In monocytes, there was downregulation of STXBP4, PIK3C3, PTPN11 and TFPI. The upregulation of platelet TF is a potentially important finding and is associated with possible compensatory up-regulation of TFPI, the principal TF inhibitor present in platelets and megakaryocytes, and GSK3B, a negative regulator of TF synthesis. To confirm this, we studied TF protein from the same subject. In isolated platelets and monocytes TF antigen (ELISA) increased 2-fold (8 to 16 pg/mg protein) and 5-fold (0.6 to 2.9 pg/mg), respectively. In addition, TF-PCA in whole blood increased (7.9 to 69.7 u/mL) over 24 h. Because of limited protein available, we were only able to immunoblot for GSKb3 (↑∼34%) and PTPN11 (↑∼42%). Taken together, these studies support the hypothesis that HG+HI, even in the non-diabetic state, induces demonstrable changes in platelets including alterations in insulin-signaling and coagulation pathways. Further studies in healthy subjects and DM patients will validate and better define these alterations and their cumulative prothrombotic effects. Table 1. Expression Profile and qRT-PCR Fold Changes for Selected Insulin Receptor Signaling and Coagulation Transcripts Gene Symbol Gene Title Platelets Monocytes Fold Change Expression (24 vs. 0 hrs) Fold Change qRT-PCR (24hrs vs. 0 hours and 4) Normals Fold Change Expression (24 vs. 0 hrs) Fold Change qRT-PCR (24 vs. 0 hrs) IRS1 Insulin receptor substrate 1 0.14 2.451 (2.27, 2.64) 0.73 0.88 (0.72, 1.08) INSR Insulin receptor 0.23 1.00 (0.83, 1.21) 0.89 0.88* (0.86, 0.91) GSK3B Glycogen synthase kinase 3 beta 5.51 1.62* (1.52, 1.74) 1.05 0.87 (0.83, 0.91) F3 Tissue factor 3.74 7.08* (1.08, 46.32) 0.40 1.12 (1.01, 1.23) TFPI Tissue factor pathway inhibitor 4.48 1.30* (1.26, 1.35) 0.79 0.66* (0.56, 0.79) VAMP2 Vesicle-associated membrane protein 2 14.29 0.82 (0.75, 0.89) 0.86 0.85* (0.83, 0.86) STXBP4 Syntaxin binding protein 4 0.13 0.87* (0.87, 0.88) 0.97 0.91* (0.83, 0.99) PIK3C3 Phosphoinositide-3-kinase class 3 0.31 1.37 (1.31, 1.44) 0.16 0.81* (0.75, 0.87) PTPN11 Protein tyrosine phosphatase, non-receptor type II 13.00 1.97* (1.56, 2.49) 0.60 0.65* (0.65, 0.65) Disclosures: No relevant conflicts of interest to declare.
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Scharl, Michael, Kacper A. Wojtal, Anne Fischbeck, Joba M. Arikkat, Theresa Pesch, Silvia Kellermeier, Stephan R. Vavricka, Michael Fried, Declan F. McCole, and Gerhard Rogler. "The Crohn's Disease Candidate Gene, Protein Tyrosine Phosphatase Non-Receptor Type 2, Regulates Muramyldipetide-Induced NOD2-Dependent Effects in Human Monocytes and Fibroblasts." Gastroenterology 140, no. 5 (May 2011): S—487. http://dx.doi.org/10.1016/s0016-5085(11)62007-6.
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Martin, Leenus, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, and Robert Shoemaker. "Abstract 2670: ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC tumor models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2670. http://dx.doi.org/10.1158/1538-7445.am2022-2670.
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Abstract ERAS-601 is a potent, small molecule allosteric inhibitor of wildtype SHP2, a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. ERAS-601 inhibits wild type SHP2 biochemically with an IC50 of 4.6 nM and demonstrates selectivity across panels of 300 kinases and 12 phosphatases. SHP2 mediates upstream receptor tyrosine kinase (RTK) signaling via its phosphatase-mediated regulation of guanine nucleotide exchange factors (GEFs). ERAS-601 inhibits the SHP2 dependent cycling of KRAS from the inactive GDP-bound state to the active GTP-bound state and demonstrates anti-proliferative activity in KRASG12C and EGFR amplified cell lines. The combination of upstream blockade of RAS-GTP cycling by ERAS-601 with inhibition of KRASG12C by a selective KRASG12C inhibitor synergistically inhibits cellular proliferation in multiple KRASG12C mutated human cancer cell lines. The combinations of ERAS-601 with KRASG12C inhibitors achieve tumor growth inhibition that is superior to the respective ERAS-601 and KRASG12C monotherapies in NSCLC and CRC CDX and PDX tumor models. Similarly, the combination of ERAS-601 with an EGFR antibody, cetuximab, inhibits oncogenic RAS/MAPK signaling as measured by pERK1/2 and enhances the anti-proliferative activity of cetuximab in RAS/RAF wild type CRC and HPV-negative HNSCC cell lines. The combination of ERAS-601 with cetuximab achieves tumor growth inhibition that is superior to respective ERAS-601 and cetuximab monotherapies in RAS/RAF wild type CRC and HPV-negative HNSCC CDX and PDX tumor models. These nonclinical data support the clinical development of ERAS-601 in combination with a KRASG12C inhibitor in NSCLC and CRC tumors, and ERAS-601 in combination with cetuximab in RAS/RAF wild type CRC as well as HPV-negative HNSCC tumors. Both combinations are being studied in ongoing clinical studies (HERKULES-2, NCT04959981; FLAGSHP-1, NCT04670679). Citation Format: Leenus Martin, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker. ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC tumor models [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 2670.
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Chen, Lili, Wei Chen, Maria Mysliwski, Justin Serio, James Ropa, Fardokht Abulwerdi, Rebecca J. Chan, et al. "Hyperactive Ptpn11 Mutations Alters Leukemic Stem Cell Frequency through Mcl-1 Overexpression." Blood 124, no. 21 (December 6, 2014): 3565. http://dx.doi.org/10.1182/blood.v124.21.3565.3565.
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Abstract Shp2 is a non-receptor protein-tyrosine phosphatase encoded by PTPN11 and implicated in the Ras, JAK-STAT and PI3K pathways. Activating mutations in Shp2 are found in patients with developmental disorders such as Noonan and LEOPARD syndrome, as well as, hematologic malignancies. Although rare in most other solid tumors, Shp2 mutations are common in juvenile myelomonocytic leukemia (JMML) accounting for ~35% of cases. To understand its role as a cooperating mutation in AML we sequenced PTPN11 in human samples. Here we report that Shp2 mutations are present in human AML at a rate of 6.6% (6/91) in the ECOG E1900 dataset. To investigate the biological function of Shp2 mutations we asked how this functions in a cooperative model of leukemogenesis with the MLL-AF9 fusion protein. Despite showing increased genetic stability compared to other leukemias, MLL leukemias commonly contain type I mutations that can functionally cooperate resulting in more aggressive leukemias. These mutations often occur in genes encoding components of the Ras pathway including mutually exclusive mutations of NRAS, KRAS, PTPN11 and NF1 and account for ~37% of MLL rearranged leukemias. However, the mechanisms of cooperation with MLL fusion proteins are poorly understood. We found that the Shp2E76K activating mutation commonly found in humans significantly accelerates MLL-AF9 mediated leukemogenesis. The E76K mutation results in structural changes that confer increased phosphatase activity to the Shp2 protein and increased Ras signaling. We attribute the MLL-AF9/Shp2E76K cooperation to a more rapid leukemic initiation as evidenced in colony formation assays using mouse bone marrow HSPCs. Cells transduced with MLL-AF9/Shp2E76K expanded faster than MLL-AF9 cells at early stages following transduction, indicating more efficient transformation of myeloid progenitors than MLL-AF9 alone. Cytokine independent growth is achieved in MLL-AF9 cells following expression of Shp2E76K through the constitutive activation of the IL3 signaling pathway and ERK phosphorylation. Importantly, addition of Shp2E76K significantly accelerated MLL-AF9 mediated acute myeloid leukemia in mice, indicating activated Shp2 cooperates with MLL-AF9 in vivo. In addition, leukemic stem cell frequency was increased by greater than 4 fold due to Shp2E76K expression. As Shp2 is reported to regulate an anti-apoptotic gene program, we investigated these in the context of MLL-AF9 leukemic cells with and without Shp2E76K. While Bcl2, BclXL and Mcl-1, were upregulated in Shp2E76K cells, Mcl-1 showed the highest upregulation in response to Shp2E76K. Further, expression of Mcl-1 with MLL-AF9 in colony assays phenocopies expression of Shp2E76K suggesting that, mechanistically, Shp2 mutations may cooperate through activation of an anti-apoptotic gene program, primarily through Mcl-1. Finally, we asked how leukemic cells bearing Shp2E76K would respond to small molecule inhibition of Mcl-1. MLL-AF9 leukemic cells expressing Shp2E76K were desensitized to small molecule mediated Mcl-1 inhibition consistent with increased Mcl-1 protein. These data were confirmed in human cells where U937 cells, which contain an activating Shp2 mutation, exhibited resistance to Mcl-1 inhibition compared to ML2 or K562 cell which both bear wild type Shp2. Together, these data suggest patients with hyperactive Shp2 signaling may respond poorly to drugs targeting Mcl-1 due to an overabundance of the protein. Disclosures No relevant conflicts of interest to declare.
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Quintanar-Audelo, Martina, Permeen Yusoff, Saravanan Sinniah, Sumana Chandramouli, and Graeme R. Guy. "Sprouty-related Ena/Vasodilator-stimulated Phosphoprotein Homology 1-Domain-containing Protein (SPRED1), a Tyrosine-Protein Phosphatase Non-receptor Type 11 (SHP2) Substrate in the Ras/Extracellular Signal-regulated Kinase (ERK) Pathway." Journal of Biological Chemistry 286, no. 26 (April 29, 2011): 23102–12. http://dx.doi.org/10.1074/jbc.m110.212662.
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Furlan, Veronika, Janez Konc, and Urban Bren. "Inverse Molecular Docking as a Novel Approach to Study Anticarcinogenic and Anti-Neuroinflammatory Effects of Curcumin." Molecules 23, no. 12 (December 18, 2018): 3351. http://dx.doi.org/10.3390/molecules23123351.
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Research efforts are placing an ever increasing emphasis on identifying signal transduction pathways related to the chemopreventive activity of curcumin. Its anticarcinogenic effects are presumably mediated by the regulation of signaling cascades, including nuclear factor κB (NF-κB), activator protein 1 (AP-1), and mitogen-activated protein kinases (MAPK). By modulating signal transduction pathways, curcumin induces apoptosis in malignant cells, thus inhibiting cancer development and progression. Due to the lack of mechanistic insight in the scientific literature, we developed a novel inverse molecular docking protocol based on the CANDOCK algorithm. For the first time, we performed inverse molecular docking of curcumin into a collection of 13,553 available human protein structures from the Protein Data Bank resulting in prioritized target proteins of curcumin. Our predictions were in agreement with the scientific literature and confirmed that curcumin binds to folate receptor β, DNA (cytosine-5)-methyltransferase 3A, metalloproteinase-2, mitogen-activated protein kinase 9, epidermal growth factor receptor and apoptosis-inducing factor 1. We also identified new potential protein targets of curcumin, namely deoxycytidine kinase, NAD-dependent protein deacetylase sirtuin-1 and -2, ecto-5′-nucleotidase, core histone macro-H2A.1, tyrosine-protein phosphatase non-receptor type 11, macrophage colony-stimulating factor 1 receptor, GTPase HRas, aflatoxin B1 aldehyde reductase member 3, aldo-keto reductase family 1 member C3, amiloride-sensitive amine oxidase, death-associated protein kinase 2 and tryptophan-tRNA ligase, that may all play a crucial role in its observed anticancer effects. Moreover, our inverse docking results showed that curcumin potentially binds also to the proteins cAMP-specific 3′,5′-cyclic phosphodiesterase 4D and 17-β-hydroxysteroid dehydrogenase type 10, which provides a new explanation for its efficiency in the treatment of Alzheimer’s disease. We firmly believe that our computational results will complement and direct future experimental studies on curcumin’s anticancer activity as well as on its therapeutic effects against Alzheimer’s disease.
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Williams, Bret, Alexander Taylor, Olivia Orozco, Christopher Owen, Elizabeth Kelley, Andre Lescarbeau, Kelley Shortsleeves, et al. "Abstract 3327: Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3327. http://dx.doi.org/10.1158/1538-7445.am2022-3327.
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Abstract The non-receptor protein tyrosine phosphatase SHP2 (PTPN11) plays an important role in the regulation of RAS/MAPK signal transduction downstream of growth factor receptor activation. Loss of SHP2 activity suppresses tumor cell growth, making SHP2 a potential target for cancer therapy. Here we report the discovery of GDC-1971 (formerly RLY-1971), a highly potent, selective, and orally bioavailable small-molecule SHP2 inhibitor that stabilizes SHP2 in a closed, auto-inhibited conformation. GDC-1971 potently inhibits both wild-type SHP2 (IC50 <1nM) and the E76K activating mutant (IC50 <250nM) in biochemical assays. In standard 2-dimensional and anchorage-independent growth conditions, GDC-1971 inhibits cellular proliferation in models harboring receptor tyrosine kinases (RTKs), SHP2, NF1, KRAS, or BRAF mutations in a dose-dependent manner. GDC-1971 potently inhibits the proliferation of cellular models harboring KRAS G12C or G12A mutations (median IC50 <80 nM) compared to models harboring other KRAS G12, G13 or Q61 mutations (median IC50 >1 uM), indicating a link between KRAS GTP hydrolysis and SHP2 dependency. Despite this trend, some non-KRAS G12C or G12A cell lines harboring other KRAS mutations responded to GDC-1971 in vitro, suggesting some heterogeneity in RTK/SHP2 signaling dependence in subsets of other KRAS mutants. In vivo, GDC-1971 demonstrates dose-dependent RAS/MAPK pathway inhibition and induces significant tumor-growth inhibition in human xenograft models harboring EGFR and KRAS alterations at continuous daily doses that are well tolerated. Given the reported role of SHP2 as a critical mediator of resistance to targeted therapies, we assessed the activity of GDC-1971 combinations in multiple contexts. We observed increased suppression of the MAPK signaling cascade and anti-proliferation synergy when combining GDC-1971 with EGFR, ALK, and KRAS G12C inhibitors in vitro. The observed in vitro synergy translated to dramatic anti-tumor growth effects in vivo. GDC-1971 in combination with the KRAS G12C covalent inhibitor GDC-6036 resulted in significant regressions at doses well below those required for single agent activity in a KRAS G12C-mutant NSCLC xenograft model. In rodent and dog toxicology studies, GDC-1971 is well tolerated at exposures above those required to induce regression in xenograft models. The biochemical and cellular potency and favorable pharmaceutical properties of GDC-1971 support the further clinical development in RTK/MAPK pathway altered tumors using continuous daily dosing alone and in combination with other targeted agents, including the KRAS-G12C inhibitor GDC-6036 (clinical trial NCT04449874). Citation Format: Bret Williams, Alexander Taylor, Olivia Orozco, Christopher Owen, Elizabeth Kelley, Andre Lescarbeau, Kelley Shortsleeves, Randy Kipp, Vy Nguyen, Erin Brophy, Jeremy Wilbur, Yong Tang, David Lanzetta, Nigel Waters, Sherri Smith, Fabrizio Giordanetto, Paul Maragakis, Jack Greismann, Lindsay Willmore, Eric Therrien, Yang Xiao, Marie Evangelista, Luca Gerosa, Eva Lin, Mark Merchant, Alfonso Arrazate, Emily Chan, Pablo Sáenz-López Larrocha, Stefan Chun, Thomas Hunsaker, Gauri Deshmukh, Christine M. Bowman, David E. Shaw, Mark Murcko, Mahesh Padval, W Patrick Walters, James Watters, Donald A. Bergstrom. Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors [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 3327.
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Tartaglia, M., and BD Gelb. "PTPN11 (protein tyrosine phosphatase, non-receptor type, 11)." Atlas of Genetics and Cytogenetics in Oncology and Haematology, no. 2 (February 2011). http://dx.doi.org/10.4267/2042/38180.
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Tabib, Avisa, Taravat Talebi, Serwa Ghasemi, Maryam Pourirahim, Niloofar Naderi, Majid Maleki, and Samira Kalayinia. "A novel stop-gain pathogenic variant in FLT4 and a nonsynonymous pathogenic variant in PTPN11 associated with congenital heart defects." European Journal of Medical Research 27, no. 1 (December 10, 2022). http://dx.doi.org/10.1186/s40001-022-00920-8.
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Abstract Background Congenital heart defects (CHDs) are the most common congenital malformations, including structural malformations in the heart and great vessels. CHD complications such as low birth weight, prematurity, pregnancy termination, mortality, and morbidity depend on the type of defect. Methods In the present research, genetic analyses via whole-exome sequencing (WES) was performed on 3 unrelated pedigrees with CHDs. The candidate variants were confirmed, segregated by PCR-based Sanger sequencing, and evaluated by bioinformatics analysis. Results A novel stop-gain c.C244T:p.R82X variant in the FLT4 gene, as well as a nonsynonymous c.C1403T:p.T468M variant in the PTPN11 gene, was reported by WES. FLT4 encodes a receptor tyrosine kinase involved in lymphatic development and is known as vascular endothelial growth factor 3. Conclusions We are the first to report a novel c.C244T variant in the FLT4 gene associated with CHDs. Using WES, we also identified a nonsynonymous variant affecting protein-tyrosine phosphatase, the non-receptor type 11 (PTPN11) gene. The clinical implementation of WES can determine gene variants in diseases with high genetic and phenotypic heterogeneity like CHDs.
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Orrego-González, Eduardo, Carlos Martin-Restrepo, and Alberto Velez-Van-Meerbeke. "Noonan Syndrome with Multiple Lentigines and PTPN11 Mutation: A Case with Intracerebral Hemorrhage." Molecular Syndromology, January 27, 2021, 1–7. http://dx.doi.org/10.1159/000512374.
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Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome, is a rare autosomal dominant disorder with an unknown prevalence. Characteristics of this disease include cutaneous, neurologic, and cardiologic abnormalities. In this case report, we present a 12-year-old girl who was admitted to the emergency department for acute-onset left weakness, unsteady gait, nausea, and vomiting. Her physical exam notably showed left side upper motor neuron signs and dysmetria. CT scan revealed an acute hemorrhage of the right thalamus. Physical exam exhibited several craniofacial dysmorphisms and lentigines. The genetic test revealed a heterozygous missense mutation in the protein tyrosine phosphatase non-receptor type 11 (<i>PTPN11</i>) gene and a variant of unknown significance of the <i>MYH11</i> gene. To the best of our knowledge, this is the first case of a patient with NSML presenting an intracerebral hemorrhage.
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Zhang, Xin, Yi Gan, Haoshuai Zhu, Zhihao Liu, Xiaojing Yao, Chao Cheng, Zhenguo Liu, Chunhua Su, and Jianyong Zou. "Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis." Frontiers in Cardiovascular Medicine 10 (January 24, 2023). http://dx.doi.org/10.3389/fcvm.2023.1112222.
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BackgroundImmune checkpoint inhibitor-related myocarditis is the deadliest complication of immunotherapy. However, the underlying pathophysiological mechanisms of its occurrence and development remain unclear. Due to the long-term lack of effective early diagnosis and treatment options, it is of great significance to understand the pathophysiological mechanism of immune checkpoint inhibitor-related myocarditis.MethodsTissue samples from three patients with immune checkpoint inhibitor-related myocarditis and three control tissue samples were collected for protein analysis. Differentially expressed proteins were screened out using quantitative proteomics technology based on TMT markers. Protein–protein interaction (PPI) and Gene Ontology (GO) functional enrichment analyses of cross-factors were subsequently performed. Combined with the PD-L1 subcellular organelle- level protein interaction network, we searched for hub proteins involved in immune checkpoint inhibitor-related myocarditis and explored potential drug sensitivity and disease correlation.ResultsA total of 306 differentially expressed proteins were identified in immune checkpoint inhibitor-related myocarditis. Enrichment analysis showed that the differentially expressed proteins were closely related to mitochondrial metabolism. By analyzing mitochondria-related proteins and PD-L1-related proteins, we found four hub proteins, mammalian target of rapamycin (mTOR), Glycogen synthase kinase 3β (GSK3β), Protein tyrosine phosphatase non-receptor type 11 (PTPN11), and Mitofusin 2 (MFN2), indicating that they are closely related to immune checkpoint inhibitor-related myocarditis. Finally, we explored potential drugs for the treatment of immune checkpoint inhibitor-related myocarditis.ConclusionMitochondrial metabolism is involved in the process of immune checkpoint inhibitor-related myocarditis, and we identified four hub proteins, which may become new biomarkers for the early diagnosis and treatment of immune checkpoint inhibitor-related myocarditis.
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van Zuydam, Natalie R., Alexander Stiby, Moustafa Abdalla, Erin Austin, Emma H. Dahlström, Stela McLachlan, Efthymia Vlachopoulou, et al. "Genome-Wide Association Study of Peripheral Artery Disease." Circulation: Genomic and Precision Medicine 14, no. 5 (October 2021). http://dx.doi.org/10.1161/circgen.119.002862.
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Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant ( P association ≤5×10 −8 ) associations with PAD in 449 548 (N cases =12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit ) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1 ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32–1.74], P diabetes =2.5×10 −9 , P interactionwithdiabetes =5.3×10 −7 ). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11–1.19], P smokers =9.3×10 −10 , P interactionwithsmoking =3.9×10 −5 ). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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"Puerarin as a Potential Drug Candidate for the Management of Type-2 Diabetes: Molecular Docking and Pharmacophore Modeling Studies." Biointerface Research in Applied Chemistry 11, no. 2 (August 20, 2020): 8751–59. http://dx.doi.org/10.33263/briac112.87518759.
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Traditional medicines have to turn out to be the most desired approach to lessen the damaging effects of type-2 diabetes and its stern problems as a result of minor effects and reduced cost. Lately, the anti-diabetic activity of Puerarin has been documented, but the mechanism of actions has not been elucidated. This study designed to assess the molecular relations obtainable between Puerarin, a compound isolated from Pueraria lobata and targeted receptors linked to Type 2 diabetes mellitus. These processes include the molecular modeling of Puerarin to 5 receptors: peroxisome proliferator-activated receptor - gamma (PPARγ), 11-β hydroxysteroid dehydrogenase type 1 (11-β HSD1), glutamine: fructose-6-phosphate amidotransferase (GFAT), protein-tyrosine phosphatase 1B (PTP1B) and mono-ADP-ribosyltransferase sirtuin-6 (SIRT6). Following the outcomes of docking of Puerarin with the five different receptor proteins, revealed that Puerarin is a potent inhibitor which binds well with the different receptors relevant to type-2 diabetes. The pharmacophore features also revealed hydrophobic interactions, hydrogen bond acceptors, and hydrogen bond donors. Hence, the results provided insights into the development of better Puerarin as a replacement to present diabetic management.
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TYCOVÁ, I., P. HRUBÁ, D. MAIXNEROVÁ, E. GIRMANOVÁ, P. MRÁZOVÁ, L. STRAŇAVOVÁ, R. ZACHOVAL, et al. "Molecular Profiling in IgA Nephropathy and Focal and Segmental Glomerulosclerosis." Physiological Research, February 18, 2018, 93–105. http://dx.doi.org/10.33549/physiolres.933670.
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The aim of the study was to characterize by molecular profiling two glomerular diseases: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) and to identify potential molecular markers of IgAN and FSGS progression. The expressions of 90 immune-related genes were compared in biopsies of patients with IgAN (n=33), FSGS (n=17) and in controls (n=11) using RT-qPCR. To identify markers of disease progression, gene expression was compared between progressors and non-progressors in 1 year follow-up. The results were verified on validation cohort of patients with IgAN (n=8) and in controls (n=6) using laser-capture microdissection, that enables to analyze gene expression separately for glomeruli and interstitium. In comparison to controls, patients with both IgAN and FSGS, had lower expression of BAX (apoptotic molecule BCL2-associated protein) and HMOX-1 (heme oxygenase 1) and higher expression of SELP (selectin P). Furthermore, in IgAN higher expression of PTPRC (protein-tyrosine phosphatase, receptor-type C) and in FSGS higher expression of BCL2L1 (regulator of apoptosis BCL2-like 1) and IL18 compared to control was observed. Validation of differentially expressed genes between IgAN and controls on another cohort using laser-capture microdissection confirmed higher expression of PTPRC in glomeruli of patients with IgAN. The risk of progression in IgAN was associated with higher expression EDN1 (endothelin 1) (AUC=0.77) and FASLG (Fas ligand) (AUC=0.82) and lower expression of VEGF (vascular endothelial growth factor) (AUC=0.8) and in FSGS with lower expression of CCL19 (chemokine (C-C motif) ligand 19) (AUC=0.86). Higher expression of EDN1 and FASLG along with lower expression of VEGF in IgAN and lower expression of CCL19 in FSGS at the time of biopsy can help to identify patients at risk of future disease progression.
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Hayashi, Shinya, Tsukasa Matsubara, Koji Fukuda, Toshihisa Maeda, Keiko Funahashi, Marowa Hashimoto, Yoshinori Takashima, et al. "A genome-wide association study identifying single nucleotide polymorphisms in the PPFIBP2 gene was predictive for interstitial lung disease in rheumatoid arthritis patients." Rheumatology Advances in Practice, October 29, 2022. http://dx.doi.org/10.1093/rap/rkac088.
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Abstract Objective Genetic polymorphisms may serve as useful prognostic markers for the timely diagnosis of rheumatoid arthritis (RA). The purpose of this study was to identify genomic factors predictive of the occurrence of interstitial lung disease (ILD) in RA by performing a genome-wide association study (GWAS) of genetic variants, including single nucleotide polymorphisms (SNPs). Methods The study population included 306 RA patients. All patients were treated with conventional disease-modifying anti-rheumatic drugs (DMARDs), including 6–16 mg methotrexate per week. Clinical data and venous blood samples of all patients were collected prior to administering DMARDs. A total of 278,347 SNPs were analyzed to determine their association with ILD occurrence. Results Several SNPs were strongly associated with ILD occurrence (p < 1 0 −5). rs6578890, which is located on chromosome 11 in the intronic region of the gene encoding tyrosine phosphatase receptor type F polypeptide-interacting protein-binding protein 2 (PPFIBP2), showed the strongest association with ILD occurrence (odds ratio 4.32, p = 1 0 −7.93). Conclusion PPFIBP2 could be a useful genetic marker for interstitial pneumonia occurrence in RA patients and may help identify the risk of ILD occurrence prior to RA treatment, thereby improving patient outcomes. Lay summary What does this mean for patients ? Interstitial lung disease (ILD), or non-infectious pneumonia, belongs to a class of lung diseases commonly characterized by thickening and scarring of tissue. ILD can lead to morbidity and mortality due to problems with gas exchange between the lungs and the blood. Genetic polymorphisms, which are variations in DNA sequences between different people, may serve as a predictive marker of disease and help with faster diagnosis. A recent study reported that variations in the MUC5B gene were associated with ILD in rheumatoid arthritis patients worldwide. However, the genetic background was different among different populations. We tried to identify predictive markers of ILD in Japanese rheumatoid arthritis patients. We used a genome-wide association study to search for small variations in people’s DNA. We found that a variation of the PPFIBP2 gene had the strongest association with ILD occurrence. Testing for this variation may help doctors identify ILD occurrence before treatment for rheumatoid arthritis, which could improve patient outcomes.