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1
Lo, Roger. "Evolution of resistance to MAPK-targeted therapies." Journal of Translational Medicine 13, Suppl 1 (2015): K2. http://dx.doi.org/10.1186/1479-5876-13-s1-k2.
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You, Zhu, Shao‐Peng Liu, Jing Du, Yi‐Hua Wu, and Shi‐Zhou Zhang. "Advancements in MAPK signaling pathways and MAPK ‐targeted therapies for ameloblastoma: A review." Journal of Oral Pathology & Medicine 48, no. 3 (February 3, 2019): 201–5. http://dx.doi.org/10.1111/jop.12807.
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Khaliq and Fallahi-Sichani. "Epigenetic Mechanisms of Escape from BRAF Oncogene Dependency." Cancers 11, no. 10 (October 1, 2019): 1480. http://dx.doi.org/10.3390/cancers11101480.
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About eight percent of all human tumors (including 50% of melanomas) carry gain-of-function mutations in the BRAF oncogene. Mutated BRAF and subsequent hyperactivation of the MAPK signaling pathway has motivated the use of MAPK-targeted therapies for these tumors. Despite great promise, however, MAPK-targeted therapies in BRAF-mutant tumors are limited by the emergence of drug resistance. Mechanisms of resistance include genetic, non-genetic and epigenetic alterations. Epigenetic plasticity, often modulated by histone-modifying enzymes and gene regulation, can influence a tumor cell’s BRAF dependency and therefore, response to therapy. In this review, focusing primarily on class 1 BRAF-mutant cells, we will highlight recent work on the contribution of epigenetic mechanisms to inter- and intratumor cell heterogeneity in MAPK-targeted therapy response.
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Vališ, Karel, and Petr Novák. "Targeting ERK-Hippo Interplay in Cancer Therapy." International Journal of Molecular Sciences 21, no. 9 (May 3, 2020): 3236. http://dx.doi.org/10.3390/ijms21093236.
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Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.
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Shin, Min Hwa, Jiyoung Kim, Siyoung A. Lim, Jeongsoo Kim, and Kyung-Mi Lee. "Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade." International Journal of Molecular Sciences 21, no. 7 (April 5, 2020): 2531. http://dx.doi.org/10.3390/ijms21072531.
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The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug’s mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies.
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de la Puente, Pilar, Barbara Muz, Feda Azab, Micah Luderer, and Abdel Kareem Azab. "Molecularly Targeted Therapies in Multiple Myeloma." Leukemia Research and Treatment 2014 (April 16, 2014): 1–8. http://dx.doi.org/10.1155/2014/976567.
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Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.
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Paton, Emily L., Jacqueline A. Turner, and Isabel R. Schlaepfer. "Overcoming Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutated Tumours." Journal of Oncology 2020 (January 3, 2020): 1–14. http://dx.doi.org/10.1155/2020/1079827.
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Overactivation of the mitogen-activated protein kinase (MAPK) pathway is an important driver of many human cancers. First line, FDA-approved therapies targeting MAPK signalling, which include BRAF and MEK inhibitors, have variable success across cancers, and a significant number of patients quickly develop resistance. In recent years, a number of preclinical studies have reported alternative methods of overcoming resistance, which include promoting apoptosis, modulating autophagy, and targeting mitochondrial metabolism. This review summarizes mechanisms of resistance to approved MAPK-targeted therapies in BRAF-mutated cancers and discusses novel preclinical approaches to overcoming resistance.
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McKenna, Stephanie, and Lucía García-Gutiérrez. "Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?" International Journal of Molecular Sciences 22, no. 10 (May 12, 2021): 5115. http://dx.doi.org/10.3390/ijms22105115.
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Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.
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Ranchon, F., A. Boespflug, C. Rioufol, V. Schwiertz, L. Thomas, and S. Dalle. "New Treatments for Cutaneous Metastatic Melanoma: MAPK Pathway-Targeted and Immune Based Therapies." Anti-Cancer Agents in Medicinal Chemistry 15, no. 4 (April 28, 2015): 461–67. http://dx.doi.org/10.2174/1871520615666150101125028.
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Lee, Shannon, Jens Rauch, and Walter Kolch. "Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity." International Journal of Molecular Sciences 21, no. 3 (February 7, 2020): 1102. http://dx.doi.org/10.3390/ijms21031102.
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Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.
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Klinger, Bertram, and Nils Blüthgen. "Consequences of feedback in signal transduction for targeted therapies." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 770–75. http://dx.doi.org/10.1042/bst20140130.
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Over the last two decades, many small-molecule inhibitors that target kinase signalling have been developed. More than 20 of these inhibitors are FDA (U.S. Food and Drug Administration)-approved and are now being used in the clinics to treat tumours; even more have entered clinical trials. However, resistance to these inhibitors, either intrinsic to the tumour or acquired during treatment, remains a major problem in targeted therapeutics. One of the mechanisms by which tumours become resistant is the rewiring of the signalling networks via feedback, by which the tumour cells re-activate signalling or activate alternative signalling pathways. In the present article, we review insights from recent quantitative signalling studies combining mathematical modelling and experiments that revealed how feedback rewires MAPK (mitogen-activated protein kinase)/PI3K (phosphoinositide 3-kinase) signalling upon treatment and how that affects drug sensitivity.
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Ebbesen, Saya H., Maurizio Scaltriti, Carl U. Bialucha, Natasha Morse, Edward R. Kastenhuber, Hannah Y. Wen, Lukas E. Dow, José Baselga, and Scott W. Lowe. "Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas." Proceedings of the National Academy of Sciences 113, no. 11 (February 29, 2016): 3030–35. http://dx.doi.org/10.1073/pnas.1523693113.
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Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.
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Rubin, Krista. "MAPK Pathway–Targeted Therapies: Care and Management of Unique Toxicities in Patients With Advanced Melanoma." Clinical Journal of Oncology Nursing 21, no. 6 (December 1, 2017): 699–709. http://dx.doi.org/10.1188/17.cjon.699-709.
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Pranteda, Angelina, Valentina Piastra, Lorenzo Stramucci, Deborah Fratantonio, and Gianluca Bossi. "The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments." International Journal of Molecular Sciences 21, no. 8 (April 16, 2020): 2773. http://dx.doi.org/10.3390/ijms21082773.
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Pharmacological treatment of colorectal carcinoma currently proceeds through the administration of a combination of different chemotherapeutic agents. In the case of rectal carcinoma, radiation therapy also represents a therapeutic strategy. In an attempt at translating much-needed new targeted therapy to the clinics, p38 mitogen activated protein kinase (MAPK) inhibitors have been tested in clinical trials involving colorectal carcinoma patients, especially in combination with chemotherapy; however, despite the high expectations raised by a clear involvement of the p38 MAPK pathway in the response to therapeutic treatments, poor results have been obtained so far. In this work, we review recent insights into the exact role of the p38 MAPK pathway in response to currently available therapies for colorectal carcinoma, depicting an intricate scenario in which the p38 MAPK node presents many opportunities, as well as many challenges, for its perspective exploitation for clinical purposes.
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Croce, Ferrini, Pfeffer, and Gangemi. "Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives." Cancers 11, no. 6 (June 18, 2019): 846. http://dx.doi.org/10.3390/cancers11060846.
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Among Uveal Melanoma (UM) driver mutations, those involving GNAQ or GNA11 genes are the most frequent, while a minor fraction of tumors bears mutations in the PLCB4 or CYSLTR2 genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas BRAFV600E-targeted therapy has obtained relevant results in cutaneous melanoma. However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets. In addition, BAP1 loss, which characterizes UM metastatic progression, affects chromatin structure via histone H2A deubiquitylation that may be counteracted by histone deacetylase inhibitors. Encouraging results of preclinical studies targeting signaling molecules such as MAPK and PKC were unfortunately not confirmed in early clinical studies. Indeed, a general survey of all clinical trials applying new targeted and immune therapy to UM displayed disappointing results. This paper summarizes the most recent studies of UM-targeted therapies, analyzing the possible origins of failures. We also focus on hyperexpressed molecules involved in UM aggressiveness as potential new targets for therapy.
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Patel, Sandip Pravin, Scott Morris, Young Kwang Chae, and Jeffrey Melson Clarke. "RNA turbulence by tumor type: Overexpression of actionable mRNA signaling pathways by histology." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23213-e23213. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23213.
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e23213 Background: Overexpression of mRNA provides an oncogenic mechanism, downstream of DNA level changes detected by sequencing, that can be treated with targeted therapies. It is still unknown why a subset of patients experience substantial responses to targeted therapies, while others experience minimal benefit. We hypothesize that the occurrence of multiple mRNA drivers may segment by cancer type in a similar manner to mutation burden. Methods: We examined results from 2088 patients with the 23 most common histologies that had received molecular testing at Paradigm Diagnostics by a panel of 56 mRNA targets, including 21 from the MAPK pathway, 14 from the P53 pathway, and 18 from the PI3K pathway. We calculated RNA turbulence, defined as the number of mRNA overexpressed in each case, as well as the pathway-specific RNA turbulence for the MAPK, PI3K and TP53 pathways. Results: Significant differences in overall and pathway-specific RNA turbulence across cancer types was observed. Colon and rectal cancers had high turbulence in the MAPK and TP53 pathways, with 87% having multiple putative drivers in the MAPK pathway and 29% having multiple drivers in the PI3K pathway. Small cell lung cancer and kidney cancers had high turbulence in the PI3K pathway, with 33% and 39% having multiple RNA drivers respectively. Overall, pancreatic, kidney and colon cancers had the highest turbulence and GIST, melanoma and cholangiocarcinoma had the lowest. There was a slight inverse relationship in tumor type when ranked by mutation burden vs. RNA turbulence Conclusions: RNA turbulence represents a unique mechanism by which to analyze tumors and correlates with disease type. Multiplex diagnostics assaying DNA, RNA, and protein level tumor changes will likely be needed to guide cancer therapeutics.
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Kancherla, Jayaram, Shruti Rao, Krithika Bhuvaneshwar, Rebecca B. Riggins, Robert A. Beckman, Subha Madhavan, Héctor Corrada Bravo, and Simina M. Boca. "Evidence-Based Network Approach to Recommending Targeted Cancer Therapies." JCO Clinical Cancer Informatics, no. 4 (September 2020): 71–88. http://dx.doi.org/10.1200/cci.19.00097.
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PURPOSE In this work, we introduce CDGnet (Cancer-Drug-Gene Network), an evidence-based network approach for recommending targeted cancer therapies. CDGnet represents a user-friendly informatics tool that expands the range of targeted therapy options for patients with cancer who undergo molecular profiling by including the biologic context via pathway information. METHODS CDGnet considers biologic pathway information specifically by looking at targets or biomarkers downstream of oncogenes and is personalized for individual patients via user-inputted molecular alterations and cancer type. It integrates a number of different sources of knowledge: patient-specific inputs (molecular alterations and cancer type), US Food and Drug Administration–approved therapies and biomarkers (curated from DailyMed), pathways for specific cancer types (from Kyoto Encyclopedia of Genes and Genomes [KEGG]), gene-drug connections (from DrugBank), and oncogene information (from KEGG). We consider 4 different evidence-based categories for therapy recommendations. Our tool is delivered via an R/Shiny Web application. For the 2 categories that use pathway information, we include an interactive Sankey visualization built on top of d3.js that also provides links to PubChem. RESULTS We present a scenario for a patient who has estrogen receptor (ER)–positive breast cancer with FGFR1 amplification. Although many therapies exist for patients with ER-positive breast cancer, FGFR1 amplifications may confer resistance to such treatments. CDGnet provides therapy recommendations, including PIK3CA, MAPK, and RAF inhibitors, by considering targets or biomarkers downstream of FGFR1. CONCLUSION CDGnet provides results in a number of easily accessible and usable forms, separating targeted cancer therapies into categories in an evidence-based manner that incorporates biologic pathway information.
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Motti, Maria Letizia, Michele Minopoli, Gioconda Di Carluccio, Paolo Antonio Ascierto, and Maria Vincenza Carriero. "MicroRNAs as Key Players in Melanoma Cell Resistance to MAPK and Immune Checkpoint Inhibitors." International Journal of Molecular Sciences 21, no. 12 (June 26, 2020): 4544. http://dx.doi.org/10.3390/ijms21124544.
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Advances in the use of targeted and immune therapies have revolutionized the clinical management of melanoma patients, prolonging significantly their overall and progression-free survival. However, both targeted and immune therapies suffer limitations due to genetic mutations and epigenetic modifications, which determine a great heterogeneity and phenotypic plasticity of melanoma cells. Acquired resistance of melanoma patients to inhibitors of BRAF (BRAFi) and MEK (MEKi), which block the mitogen-activated protein kinase (MAPK) pathway, limits their prolonged use. On the other hand, immune checkpoint inhibitors improve the outcomes of patients in only a subset of them and the molecular mechanisms underlying lack of responses are under investigation. There is growing evidence that altered expression levels of microRNAs (miRNA)s induce drug-resistance in tumor cells and that restoring normal expression of dysregulated miRNAs may re-establish drug sensitivity. However, the relationship between specific miRNA signatures and acquired resistance of melanoma to MAPK and immune checkpoint inhibitors is still limited and not fully elucidated. In this review, we provide an updated overview of how miRNAs induce resistance or restore melanoma cell sensitivity to mitogen-activated protein kinase inhibitors (MAPKi) as well as on the relationship existing between miRNAs and immune evasion by melanoma cell resistant to MAPKi.
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Bonaldi, Elisa, Chiara Gargiuli, Loris De Cecco, Arianna Micali, Maria Grazia Rizzetti, Angela Greco, Maria Grazia Borrello, and Emanuela Minna. "BRAF Inhibitors Induce Feedback Activation of RAS Pathway in Thyroid Cancer Cells." International Journal of Molecular Sciences 22, no. 11 (May 27, 2021): 5744. http://dx.doi.org/10.3390/ijms22115744.
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BRAFV600E is the most frequent oncogenic mutation identified in papillary thyroid cancer (PTC). In PTC patients who do not respond to standard treatment, BRAF inhibitors are currently tested as alternative strategies. However, as observed for other targeted therapies, patients eventually develop drug resistance. The mechanisms of BRAF inhibitors response are still poorly understood in a thyroid cancer (TC) context. In this study, we investigated in BRAFV600E mutated TC cell lines the effects of Vemurafenib and Dabrafenib, two BRAF inhibitors currently used in a clinical setting. We assessed cell proliferation, and the expression and activity of the thyroid function related transporter NIS following the treatment with BRAF inhibitors. In addition, we investigated the global gene expression by microarray, the relevant modulated biological processes by gene set enrichment analysis (GSEA), and TC specific gene signatures related to MAPK pathway activation, thyroid differentiation, and transcriptional profile associated with BRAFV600E or RAS mutation. We found that both inhibitors induce antiproliferative and redifferentiative effects on TC cells, as well as a rewiring of the MAPK pathway related to RAS signaling. Our results suggest a possible mechanism of drug response to the BRAF inhibitors Vemurafenib or Dabrafenib, supporting very recent findings in TC patients treated with targeted therapies.
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Alijaj, Nagjie, Sandrine Moutel, Zelia L. Gouveia, Maxim Gray, Maurizio Roveri, Dzhangar Dzhumashev, Florian Weber, et al. "Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma." Cancers 12, no. 11 (November 10, 2020): 3313. http://dx.doi.org/10.3390/cancers12113313.
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The fibroblast growth factor receptor 4 (FGFR4) is overexpressed in rhabdomyosarcoma (RMS) and represents a promising target for treatments based on specific and efficient antibodies. Despite progress, there is an urgent need for targeted treatment options to improve survival rates, and to limit long-term side effects. From phage display libraries we selected FGFR4-specific single-domain antibodies (sdAb) binding to recombinant FGFR4 and validated them by flow cytometry, surface plasmon resonance, and fluorescence microscopy. The specificity of the selected sdAb was verified on FGFR4-wild type and FGFR4-knock out cells. FGFR4-sdAb were used to decorate vincristine-loaded liposomes and to generate chimeric antigen receptor (CAR) T cells. First, incubation of RMS cells with FGFR4-sdAb revealed that FGFR4-sdAb can block FGF19-FGFR4 signaling via the MAPK pathway and could therefore serve as therapeutics for FGFR4-dependent cancers. Second, FGFR4-targeted vincristine-loaded liposomes bound specifically to RMS cells and were internalized by the receptor, demonstrating the potential for active drug delivery to the tumor. Third, FGFR4-CAR T cells, generated with one sdAb candidate, demonstrated strong and specific cytotoxicity against FGFR4 expressing RMS cells. We selected novel FGFR4-sdAb with high specificity and nano- to picomolar affinities for FGFR4 which have the potential to enable multiple FGFR4-targeted cancer therapy approaches.
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Chauhan, Shreepa J., Anita Thyagarajan, Yanfang Chen, Jeffrey B. Travers, and Ravi P. Sahu. "Platelet-Activating Factor-Receptor Signaling Mediates Targeted Therapies-Induced Microvesicle Particles Release in Lung Cancer Cells." International Journal of Molecular Sciences 21, no. 22 (November 12, 2020): 8517. http://dx.doi.org/10.3390/ijms21228517.
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Microvesicle particles (MVP) secreted by a variety of cell types in response to reactive oxygen species (ROS)-generating pro-oxidative stressors have been implicated in modifying the cellular responses including the sensitivity to therapeutic agents. Our previous studies have shown that expression of a G-protein coupled, platelet-activating factor-receptor (PAFR) pathway plays critical roles in pro-oxidative stressors-mediated cancer growth and MVP release. As most therapeutic agents act as pro-oxidative stressors, the current studies were designed to determine the role of the PAFR signaling in targeted therapies (i.e., gefitinib and erlotinib)-mediated MVP release and underlying mechanisms using PAFR-expressing human A549 and H1299 non-small cell lung cancer (NSCLC) cell lines. Our studies demonstrate that both gefitinib and erlotinib generate ROS in a dose-dependent manner in a process blocked by antioxidant and PAFR antagonist, verifying their pro-oxidative stressor’s ability, and the role of the PAFR in this effect. We observed that these targeted therapies induce MVP release in a dose- and time-dependent manner, similar to a PAFR-agonist, carbamoyl-PAF (CPAF), and PAFR-independent agonist, phorbol myristate acetate (PMA), used as positive controls. To confirm the PAFR dependency, we demonstrate that siRNA-mediated PAFR knockdown or PAFR antagonist significantly blocked only targeted therapies- and CPAF-mediated but not PMA-induced MVP release. The use of pharmacologic inhibitor strategy suggested the involvement of the lipid ceramide-generating enzyme, acid sphingomyelinase (aSMase) in MVP biogenesis, and observed that regardless of the stimuli used, aSMase inhibition significantly blocked MVP release. As mitogen-activated protein kinase (MAPK; ERK1/2 and p38) pathways crosstalk with PAFR, their inhibition also significantly attenuated targeted therapies-mediated MVP release. These findings indicate that PAFR signaling could be targeted to modify cellular responses of targeted therapies in lung cancer cells.
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Scheiblecker, Lisa, Karoline Kollmann, and Veronika Sexl. "CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment." Pharmaceuticals 13, no. 12 (November 24, 2020): 418. http://dx.doi.org/10.3390/ph13120418.
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Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer and signify vulnerable nodes and potential therapeutic targets. We here focus on the cell cycle kinase CDK6 and on the MAPK pathway and on their interplay. We also provide an overview on clinical studies examining the effects of combinational treatments currently explored for several cancer types.
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Cohen Aubart, Fleur, Ahmed Idbaih, Jean-François Emile, Zahir Amoura, Omar Abdel-Wahab, Benjamin H. Durham, Julien Haroche, and Eli L. Diamond. "Histiocytosis and the nervous system: from diagnosis to targeted therapies." Neuro-Oncology 23, no. 9 (May 16, 2021): 1433–46. http://dx.doi.org/10.1093/neuonc/noab107.
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Abstract Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The identification of the pivotal role of the mitogen-activated protein kinase (MAPK) pathway has opened new avenues of research and therapeutic approaches. We review the neurologic manifestations of 3 histiocytic disorders with frequent involvement of the brain and spine: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman-Destombes disease (RDD). Central nervous system (CNS) manifestations occur in 10%-25% of LCH cases, with both tumorous or neurodegenerative forms. These subtypes differ by clinical and radiological presentation, pathogenesis, and prognosis. Tumorous or degenerative neurologic involvement occurs in 30%-40% of ECD patients and affects the hypothalamic-pituitary axis, meninges, and brain parenchyma. RDD lesions are typically tumorous with meningeal or parenchymal masses with strong contrast enhancement. Unlike LCH and ECD, neurodegenerative lesions or syndromes have not been described with RDD. Familiarity with principles of evaluation and treatment both shared among and distinct to each of these 3 diseases is critical for effective management. Refractory or disabling neurohistiocytic involvement should prompt the consideration for use of targeted kinase inhibitor therapies.
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McKeown, Tara, Irene Lara-Corrales, and Andrea Cote. "NURS-04. COMBINATION OF NEURO-ONCOLOGY AND DERMATOLOGY CLINICS IMPROVE THE MANAGEMENT AND KNOWLEDGE OF SKIN-RELATED TOXICITIES WITH MEK AND BRAF TARGETED THERAPY." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii421—iii422. http://dx.doi.org/10.1093/neuonc/noaa222.624.
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Abstract BACKGROUND The recent advancement in treating pediatric low grade glioma has led to upfront use of MEK and BRAF (MAPK) inhibitor therapy. At the Hospital for Sick Children we are the National leaders in treating pediatric oncology diagnosis with MAPK therapies. DESIGN: After treating several patients on MAPK inhibitors with various degrees of skin toxicity, we found we had poor and inconsistent access to dermatology services and as oncology practitioners had limited front-line knowledge about skin management. It was determined that a more formalized expertise and time with dermatology was needed. In 2018, in combination with the dermatology team, our new agents and innovative therapy and the nursing team we collaborated to develop a combined oncology and dermatology clinic. This clinic occurs twice a month to give our families and oncology teams better front-line access to dermatology knowledge and care. RESULTS The dermatology and oncology team have collaborated to provide information sessions for the oncology medical team about current research, skin grading and education. This combined approach has allowed us to ensure that each new family starting MAPK inhibitor therapy undergoes a baseline skin assessment, education on prophylactic skin measures and easier access to dermatology within their oncology clinic. We are also developing guidelines to consistently treat common skin related toxicities. CONCLUSION The early involvement of the dermatology clinic and increase knowledge with the nursing and medical team has allowed our families to gain confidence in managing skin related complication and reducing the need to hold targeted therapies as a result of dermatological toxicity.
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Voskoboynik, Mark, and Hendrik-Tobias Arkenau. "Combination Therapies for the Treatment of Advanced Melanoma: A Review of Current Evidence." Biochemistry Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/307059.
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The treatment of advanced melanoma has been revolutionised in recent years with the advent of a range of new therapies. BRAF inhibitors, such as vemurafenib, have demonstrated improvements in the overall survival of patients with advanced melanoma that harbour a BRAF V600 mutation. Alongside these targeted therapies, novel immune-checkpoint inhibitors, such as ipilimumab, have also been developed and have produced similarly improved outcomes for patients. For the first time in the history of melanoma, monotherapy with each of these drugs has produced improvements in the overall survival of patients with advanced disease. Building on this initial success, there has been intense interest in developing combination therapies predominantly with either dual blockade of the MAPK oncogenic pathway or dual immune-checkpoint blockade. The current evidence for the use of these combination therapies will be presented here.
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Bellio, Helene, Jean David Fumet, and Francois Ghiringhelli. "Targeting BRAF and RAS in Colorectal Cancer." Cancers 13, no. 9 (May 3, 2021): 2201. http://dx.doi.org/10.3390/cancers13092201.
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Colorectal cancer (CRC) is still one of the most frequent forms of cancer in the world in terms of incidence. Around 40% of CRC patients carry a mutation of the Kirsten rat sarcoma (KRAS) gene, while 10% have a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene. These mutations are responsible for dysregulation of the mitogen-associated protein kinase (MAPK) pathway, leading to the proliferation, differentiation, angiogenesis, and resistance to apoptosis of cells. Activation of the MAPK pathway results in adaptive therapeutic resistance, rendering EGFR inhibitors ineffective. This review aims to highlight the recent findings that have improved our understanding of KRAS and BRAF mutations in colorectal cancer and to describe new targeted therapies, used alone or in combination.
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Proietti, Ilaria, Nevena Skroza, Simone Michelini, Alessandra Mambrin, Veronica Balduzzi, Nicoletta Bernardini, Anna Marchesiello, et al. "BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions." Cancers 12, no. 7 (July 7, 2020): 1823. http://dx.doi.org/10.3390/cancers12071823.
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The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signalling pathway that regulates the proliferation and survival of melanoma cells. In addition to their molecularly targeted activity, BRAF inhibitors have immunomodulatory effects. The MAPK pathway is involved in T-cell receptor signalling, and interference in the pathway by BRAF inhibitors has beneficial effects on the tumour microenvironment and anti-tumour immune response in BRAF-mutant melanoma, including increased immune-stimulatory cytokine levels, decreased immunosuppressive cytokine levels, enhanced melanoma differentiation antigen expression and presentation of tumour antigens by HLA 1, and increased intra-tumoral T-cell infiltration and activity. These effects promote recognition of the tumour by the immune system and enhance anti-tumour T-cell responses. Combining BRAF inhibitors with MEK inhibitors provides more complete blockade of the MAPK pathway. The immunomodulatory effects of BRAF inhibition alone or in combination with MEK inhibition provide a rationale for combining these targeted therapies with immune checkpoint inhibitors. Available data support the synergy between these treatment approaches, indicating such combinations provide an additional beneficial effect on the tumour microenvironment and immune response in BRAF-mutant melanoma.
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Guiho, Romain, Florian Selt, Thomas Stone, Thomas Jacques, Darren Hargrave, Jesús Gil, Olaf Witt, Till Milde, and Juan Pedro Martinez Barbera. "LGG-09. SENOLYTIC AGENT NAVITOCLAX TARGETS VINBLASTINE- AND MAPK INHIBITORS-INDUCED SENESCENT TUMOUR CELLS IN PAEDIATRIC LOW GRADE GLIOMAS." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i33. http://dx.doi.org/10.1093/neuonc/noab090.133.
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Abstract Pilocytic astrocytoma (PA, WHO grade I), the most common paediatric brain tumour, is characterized by constitutive activation of the MAPK pathway. PA tumours show a slow growth, without tendency to progress to high-grade malignancies. However, a significant group of patients for whom a total resection is not feasible require additional therapy. The typical proliferative index of a PA, measured by Ki-67 staining, is 1–2%, whereas a large part of the tumour is Ki-67 negative and expresses markers of oncogene-induced senescence (OIS) such as SA-β-Gal positivity and the cell cycle inhibitors p16INK4a (CDKN2A) and p21Cip1 (CDKN1A). Conventional treatments (i.e. chemotherapy) tend to target only proliferative cells and the effect of new molecularly targeted therapies (e.g., MAPK pathway inhibitors) on senescent cells remains unclear. Here, we discuss the opportunities to combine these therapies with new compounds targeting the senescent cells, referred to as senolytics, using three different PA models. (1) Ex vivo culture of human PA tumours (2) Two cell lines: the DKFZ-BT66 PA human cell line, carrying the oncogenic driver KIAA1549:BRAF-fusion, used as a model of OIS; and the proliferative BT40 cell line harbouring the BRAFV600E mutation; (3) In vivo xenograft model induced by orthotopic transplantation of BT40 cells. We have previously shown that OIS cells exhibit an increased sensitivity to senolytic compounds, such as navitoclax, a clinically approved BCL2/XL inhibitor, relative to proliferative controls (Buhl et al, Clin Cancer Res. 2019). Our current research demonstrates that treatments with low doses of chemotherapy (e.g., vinblastine) or MAPK inhibitors (e.g., dabrafenib or trametinib) triggers a therapy-induced senescence response in proliferative cells (e.g., abolished proliferation, SA-β-Gal positivity, SASP production), making these senescent cells sensitive to senolytic compounds, including navitoclax. Together, our research provides a strong rationale supporting the combined use of senolytics with current conventional and targeted therapies against human PA.
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Wurm, Julian, Simon P. Behringer, Vidhya M. Ravi, Kevin Joseph, Nicolas Neidert, Julian P. Maier, Roberto Doria-Medina, et al. "Astrogliosis Releases Pro-Oncogenic Chitinase 3-Like 1 Causing MAPK Signaling in Glioblastoma." Cancers 11, no. 10 (September 26, 2019): 1437. http://dx.doi.org/10.3390/cancers11101437.
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Although reactive astrocytes constitute a major component of the cellular environment in glioblastoma, their function and crosstalk to other components of the environment is still poorly understood. Gene expression analysis of purified astrocytes from both the tumor core and non-infiltrated cortex reveals a tumor-related up-regulation of Chitinase 3-like 1 (CHI3L1), a cytokine which is related to inflammation, extracellular tissue remodeling, and fibrosis. Further, we established and validated a co-culture model to investigate the impact of reactive astrocytes within the tumor microenvironment. Here we show that reactive astrocytes promote a subtype-shift of glioblastoma towards the mesenchymal phenotype, driving mitogen-activated protein kinases (MAPK) signaling as well as increased proliferation and migration. In addition, we demonstrate that MAPK signaling is directly caused by a CHI3L1-IL13RA2 co-binding, which leads to increased downstream MAPK and AKT signaling. This novel microenvironmental crosstalk highlights the crucial role of non-neoplastic cells in malignant brain tumors and opens up new perspectives for targeted therapies in glioblastoma.
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Sullivan, Ryan, Patricia LoRusso, Scott Boerner, and Reinhard Dummer. "Achievements and Challenges of Molecular Targeted Therapy in Melanoma." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): 177–86. http://dx.doi.org/10.14694/edbook_am.2015.35.177.
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The treatment of melanoma has been revolutionized over the past decade with the development of effective molecular and immune targeted therapies. The great majority of patients with melanoma have mutations in oncogenes that predominantly drive signaling through the mitogen activated protein kinase (MAPK) pathway. Analytic tools have been developed that can effectively stratify patients into molecular subsets based on the identification of mutations in oncogenes and/or tumor suppressor genes that drive the MAPK pathway. At the same time, potent and selective inhibitors of mediators of the MAPK pathway such as RAF, MEK, and ERK have become available. The most dramatic example is the development of single-agent inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) and MEK (trametinib, cobimetinib, binimetinib) for patients with metastatic BRAFV600-mutant melanoma, a subset that represents 40% to 50% of patients with metastatic melanoma. More recently, the elucidation of mechanisms underlying resistance to single-agent BRAF inhibitor therapy led to a second generation of trials that demonstrated the superiority of BRAF inhibitor/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib) compared to single-agent BRAF inhibitors. Moving beyond BRAFV600targeting, a number of other molecular subsets—such as mutations in MEK, NRAS, and non-V600 BRAF and loss of function of the tumor suppressor neurofibromatosis 1 ( NF1)—are predicted to respond to MAPK pathway targeting by single-agent pan-RAF, MEK, or ERK inhibitors. As these strategies are being tested in clinical trials, preclinical and early clinical trial data are now emerging about which combinatorial approaches might be best for these patients.
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Park, Jae Gwang, Nur Aziz, and Jae Youl Cho. "MKK7, the essential regulator of JNK signaling involved in cancer cell survival: a newly emerging anticancer therapeutic target." Therapeutic Advances in Medical Oncology 11 (January 2019): 175883591987557. http://dx.doi.org/10.1177/1758835919875574.
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One of the mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal protein kinase (JNK) plays an important role in regulating cell fate, such as proliferation, differentiation, development, transformation, and apoptosis. Its activity is induced through the interaction of MAPK kinase kinases (MAP3Ks), MAPK kinases (MAP2Ks), and various scaffolding proteins. Because of the importance of the JNK cascade to intracellular bioactivity, many studies have been conducted to reveal its precise intracellular functions and mechanisms, but its regulatory mechanisms remain elusive. In this review, we discuss the molecular characterization, activation process, and physiological functions of mitogen-activated protein kinase kinase 7 (MKK7), the MAP2K that most specifically controls the activity of JNK. Understanding the role of MKK7/JNK signaling in physiological conditions could spark new hypotheses for targeted anticancer therapies.
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Remmerie, Michiel, and Veerle Janssens. "Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late." International Journal of Molecular Sciences 19, no. 8 (August 13, 2018): 2380. http://dx.doi.org/10.3390/ijms19082380.
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Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.
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Ilcus, Cristina, Horatiu Silaghi, Carmen Emanuela Georgescu, Carmen Georgiu, Anca Ileana Ciurea, Simona Delia Nicoara, and Cristina Alina Silaghi. "Molecular Pathology and Targeted Therapies for Personalized Management of Central Nervous System Germinoma." Journal of Personalized Medicine 11, no. 7 (July 14, 2021): 661. http://dx.doi.org/10.3390/jpm11070661.
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Intracranial germinomas are rare tumours, usually affecting male paediatric patients. They frequently develop in the pineal and suprasellar regions, causing endocrinological disturbances, visual deficits, and increased intracranial pressure. The diagnosis is established on magnetic resonance imaging (MRI), serum and cerebrospinal fluid (CSF) markers, and tumour stereotactic biopsy. Imaging techniques, such as susceptibility-weighted imaging (SWI), T2* (T2-star) gradient echo (GRE) or arterial spin labelling based perfusion-weighted MRI (ASL-PWI) facilitate the diagnosis. Germinomas are highly radiosensitive tumours, with survival rates >90% in the context of chemoradiotherapy. However, patients with resistant disease have limited therapeutic options and poor survival. The aim of this review is to highlight the genetic, epigenetic, and immunologic features, which could provide the basis for targeted therapy. Intracranial germinomas present genetic and epigenetic alterations (chromosomal aberrations, KIT, MAPK and PI3K pathways mutations, DNA hypomethylation, miRNA dysregulation) that may represent targets for therapy. Tyrosine kinase and mTOR inhibitors warrant further investigation in these cases. Immune markers, PD-1 (programmed cell death protein 1) and PD-L1 (programmed death-ligand 1), are expressed in germinomas, representing potential targets for immune checkpoint inhibitors. Resistant cases should benefit from a personalized management: genetic and immunological testing and enrolment in trials evaluating targeted therapies in intracranial germinomas.
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Diazzi, Serena, Sophie Tartare-Deckert, and Marcel Deckert. "Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies." Cancers 12, no. 6 (May 26, 2020): 1364. http://dx.doi.org/10.3390/cancers12061364.
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Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by BRAF driver mutations. Overall responses from patients with metastatic BRAF mutant melanoma are better with therapies combining BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. However, most patients that initially respond to therapies develop drug resistance within months. Acquired resistance to targeted therapies can be due to additional genetic alterations in melanoma cells and to non-genetic events frequently associated with transcriptional reprogramming and a dedifferentiated cell state. In this second scenario, it is possible to identify pro-fibrotic responses induced by targeted therapies that contribute to the alteration of the melanoma tumor microenvironment. A close interrelationship between chronic fibrosis and cancer has been established for several malignancies including breast and pancreatic cancers. In this context, the contribution of fibrosis to drug adaptation and therapy resistance in melanoma is rapidly emerging. In this review, we summarize recent evidence underlining the hallmarks of fibrotic diseases in drug-exposed and resistant melanoma, including increased remodeling of the extracellular matrix, enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues, and the establishment of an inflammatory microenvironment. We also discuss several potential therapeutic options for manipulating this fibrotic-like response to combat drug-resistant and invasive melanoma.
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Czarnecka, Anna M., Ewa Bartnik, Michał Fiedorowicz, and Piotr Rutkowski. "Targeted Therapy in Melanoma and Mechanisms of Resistance." International Journal of Molecular Sciences 21, no. 13 (June 27, 2020): 4576. http://dx.doi.org/10.3390/ijms21134576.
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The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).
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Shah, Nidhi, Andrew Walter, and Gurcharanjeet Kaur. "PATH-30. TARGETED THERAPIES FOR PEDIATRIC LOW-GRADE GLIOMAS: A CASE SERIES." Neuro-Oncology 21, Supplement_6 (November 2019): vi149. http://dx.doi.org/10.1093/neuonc/noz175.626.
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Abstract Pediatric central nervous system (CNS) malignancies are the most common malignancies of childhood. The standard treatment plan for most CNS malignancies involves surgery, chemotherapy, radiation, and/or a combination of above therapies. Unresectable symptomatic low grade gliomas, such as pilocytic astrocytomas and gangliogliomas, are slow growing tumors that are typically responsive to a single course of intravenous chemotherapy, but in select patients these WHO grade I or II tumors can recur and be refractory to multiple courses. Molecular diagnostics can offer valuable insight into the tumor microenvironment, where targeted therapies can be offered for specific actionable mutations. Here we report a case series of 3 pediatric patients, with unique CNS malignancies, currently on targeted therapies for tumor-specific somatic mutations. Patient A is a 5 year old male with unresectable Neurofibromatosis-1 related plexiform neurofibroma of the nasopharyngeal space as well as optic pathway glioma, with a mutation of the MAPK/ERK pathway. Patient B is a 6 year old male with recurrent, refractory pilocytic astrocytoma of the optic pathway and hypothalamus, with progression through several courses of intravenous chemotherapy, noted to have somatic NACC2-NTRK mutation. Patient C is a 17 year old female with unresectable, pontomedullary ganglioglioma, noted to have BRAF-V600E mutation. Patient A is treated with Selumetinib, for about 6 months, with near resolution of nasopharyngeal mass. Patient B is treated with Larotrectinib, for about 3 months, with stability of clinical symptoms. Patient C is treated with Vemurafenib, for about 10 months, with stability of lesion size and patient-reported clinical improvement. No adverse events were noted for any of these patients and all medications were administered orally. Significant improvement in quality of life was reported, as they did not have central lines or bone marrow suppression. Targeted inhibitors provide a reasonable treatment option for relapsed, refractory CNS malignancies with actionable mutations.
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Al-Jundi, Mohammad, Shilpa Thakur, Sriram Gubbi, and Joanna Klubo-Gwiezdzinska. "Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review." Cancers 12, no. 8 (July 29, 2020): 2104. http://dx.doi.org/10.3390/cancers12082104.
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The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.
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Chen, Nelson, Ávila, and Cubero. "Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link." Cells 8, no. 10 (September 28, 2019): 1172. http://dx.doi.org/10.3390/cells8101172.
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In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.
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Chen, Ming-Shan, Hsuan-Te Yeh, Yi-Zhen Li, Wen-Chun Lin, Ying-Ray Lee, Ya-Shih Tseng, and Shew-Meei Sheu. "Flavopereirine Inhibits Autophagy via the AKT/p38 MAPK Signaling Pathway in MDA-MB-231 Cells." International Journal of Molecular Sciences 21, no. 15 (July 28, 2020): 5362. http://dx.doi.org/10.3390/ijms21155362.
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Autophagy is a potential target for the treatment of triple negative breast cancer (TNBC). Because of a lack of targeted therapies for TNBC, it is vital to find optimal agents that avoid chemoresistance and metastasis. Flavopereirine has anti-proliferation ability in cancer cells, but whether it regulates autophagy in breast cancer cells remains unclear. A Premo™ Tandem Autophagy Sensor Kit was used to image the stage at which flavopereirine affects autophagy by confocal microscopy. A plasmid that constitutively expresses p-AKT and siRNA targeting p38 mitogen-activated protein kinase (MAPK) was used to confirm the related signaling pathways by Western blot. We found that flavopereirine induced microtubule-associated protein 1 light chain 3 (LC3)-II accumulation in a dose- and time-dependent manner in MDA-MB-231 cells. Confocal florescent images showed that flavopereirine blocked autophagosome fusion with lysosomes. Western blotting showed that flavopereirine directly suppressed p-AKT levels and mammalian target of rapamycin (mTOR) translation. Recovery of AKT phosphorylation decreased the level of p-p38 MAPK and LC3-II, but not mTOR. Moreover, flavopereirine-induced LC3-II accumulation was partially reduced in MDA-MB-231 cells that were transfected with p38 MAPK siRNA. Overall, flavopereirine blocked autophagy via LC3-II accumulation in autophagosomes, which was mediated by the AKT/p38 MAPK signaling pathway.
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Tsai, Jessica, Jayne Vogelzang, Cecilia Sousa, Kee Kiat Yeo, Keith Ligon, Pratiti Bandopadhayay, and Tabitha Cooney. "LGG-03. LONG-TERM FOLLOW UP OF TARGETED THERAPY IN PEDIATRIC LOW-GRADE GLIOMAS: THE DANA-FARBER/BOSTON CHILDREN’S EXPERIENCE." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i31. http://dx.doi.org/10.1093/neuonc/noab090.127.
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Abstract Background Pediatric low grade gliomas (pLGGs) are the most common central nervous system (CNS) tumor in children and characterized by alterations in the MAPK pathway. Standard of care is not well defined, and treatment has evolved over the last decade to include molecular targeted therapies. The impact of targeted agents on the natural history of pLGGs remains unknown. We present a retrospective review of patients receiving targeted agents integrated with molecular profiling. Methods We performed an IRB-approved, retrospective chart review of pLGGs treated with off-label use of dabrafenib, vemurafenib, everolimus, and trametinib at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020. Results Forty-nine patients were identified (dabrafenib n=9, everolimus n=27, trametinib n=10, and vemurafenib n=3). All patients receiving BRAF inhibitors harbored BRAF V600E mutation. Targeted agent was used as first-line therapy for 25% of patients, while for 31% of patients, targeted agent was second-line therapy. The median time from diagnosis to targeted therapy initiation was 4.76 years (0.10 – 23.77), median duration of targeted therapy was 0.79 years (0.01 – 4.87), median time to subsequent therapy post first-line targeted therapy was 0.2 years (0.01 – 3.33), and overall median follow-up for the entire cohort was 3.09 years (0.36 – 11.87). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation was 58.0%, 32.2%, and 26.9%, respectively. Survival analyses by molecular subgroup and agent were performed. Reasons for cessation of targeted therapy included toxicities, progression, and/or planned end of therapy. Conclusions Further efforts are ongoing to perform volumetric analysis of growth rates before, during, and after treatment. While targeted molecular therapies show great promise, it will be critical to understand how these agents alter the natural history of pLGGs, particularly in the context of genomic profiling.
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Kinsey, Emily N., and April KS Salama. "Metastatic Uveal Melanoma—A Review of Current Therapies and Future Directions." Oncology & Hematology Review (US) 13, no. 02 (2017): 100. http://dx.doi.org/10.17925/ohr.2017.13.02.100.
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The most common type of ocular melanoma is uveal melanoma, which includes melanomas that originate from the choroid, iris, or ciliary body. Although the survival rate for all cases of uveal melanoma is high, once metastatic disease occurs the survival rate drops dramatically. Currently no standard of care exists to guide management in metastatic uveal melanoma. The molecular biology in uveal melanoma is distinct from cutaneous melanoma. In most cases of uveal melanoma, the mitogen activated protein kinase (MAPK) pathway is activated through mutations in either GNAQ or GNA11. In uveal melanoma the most common site of metastatic disease is the liver, and a number of hepatic-directed therapies are available including surgery, radiofrequency ablation, and embolization. Conventional systemic chemotherapy has shown poor response rates in uveal melanoma. An increased understanding of the molecular genetics and intracellular signaling of uveal melanoma has led to the development of immunotherapy and targeted systemic therapies. This review will discuss the options for metastatic uveal melanoma including hepatic-directed therapies, systemic therapies, and future directions.
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Gregory, Timothy A., Lyndon B. Chumbley, John W. Henson, and Brett J. Theeler. "Adult pilocytic astrocytoma in the molecular era: a comprehensive review." CNS Oncology 10, no. 1 (March 1, 2021): CNS68. http://dx.doi.org/10.2217/cns-2020-0027.
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Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the molecular alterations in adult PA are associated with MAPK pathway dysregulation. The most common alterations are fusions of BRAF. Understanding of the mechanisms underlying this pathway has evolved substantially, heralding advancements in specific targeted therapy. Here, we review clinical and molecular features of adult PA, characteristics predicting aggressive behavior and approaches to standard and investigational therapies. We highlight epigenetic profiling and integrated diagnosis as an essential component of classifying PA.
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Aashiq, Mohamed, Deborah A. Silverman, Shorook Na’ara, Hideaki Takahashi, and Moran Amit. "Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies." Cancers 11, no. 9 (September 17, 2019): 1382. http://dx.doi.org/10.3390/cancers11091382.
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Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.
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Nagathihalli, Nagaraj S., Yugandhar Beesetty, Chanjuan Shi, and Nipun B. Merchant. "Relationship of STAT3-mediated treatment resistance on activated MAPK signaling in pancreatic cancer." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 181. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.181.
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181 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult human malignancies to treat due to its intrinsic (de novo) and extrinsic (acquired) chemoresistance. We have previously identified constitutively activated STAT3 as a mediator of treatment resistance. Src or EGFR activate STAT3 and promote STAT3 mediated tumor progression and mediate communication within the tumor microenvironment (TME). The purpose of this study was to further understand the molecular mechanisms of stromal-mediated chemoresistance in PDAC to generate new and promising targeted therapies. Methods: We characterized the expression of total and activated STAT3 and MAPK proteins in human pancreatic tissues (n=106), PDAC cell lines (n=9) and in PanIn lesions, primary PDAC and liver metastasis cell lines generated from tumors established in genetically engineered mice. Effects of STAT3 and MAPK inhibition (drug or siRNA) were assessed for phosphorylation of STAT3, Src, MAPK, EGFR and GSK3β and expression of cyclin-D1, SPARC, VEGF, fibronectin, CD31 and tumorigenicity in vitro and in vivo. Results: STAT3 activation is necessary for the malignant phenotype and affects survival in PDAC. In both human and mouse PDAC cell lines and tissues, there is an inverse correlation between activation of STAT3 on MAPK and GSK3β signaling. Inhibition of STAT3 reciprocally activated MAPK, GSK3β, Src and EGFR which led to subsequent reactivation of STAT3. Targeting both STAT3 and MAPK inhibited activation of STAT3, MAPK, GSK3β, Src, EGFR and cyclin-D1. Combined inhibition of STAT3 and MAPK overcame STAT3 mediated resistance and resulted in synergistic inhibition of tumorigenicity as well as inhibition of the tumor stroma, angiogenesis and hypoxia within the TME. Conclusions: The mechanism of STAT3-mediated treatment resistance is dependent on activation of MAPK signaling which in turn leads to reactivation of multiple oncogenic signaling pathways. Combined inhibition of STAT3 and MAPK overcomes therapeutic resistance, targets the TME and reduces tumorigenicity in PDAC. Targeting STAT3 and MAPK is a potent treatment regimen and may be a novel approach to enhance drug delivery and improve therapeutic response in PDAC.
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Osrodek, Marta, and Michal Wozniak. "Targeting Genome Stability in Melanoma—A New Approach to an Old Field." International Journal of Molecular Sciences 22, no. 7 (March 28, 2021): 3485. http://dx.doi.org/10.3390/ijms22073485.
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Despite recent groundbreaking advances in the treatment of cutaneous melanoma, it remains one of the most treatment-resistant malignancies. Due to resistance to conventional chemotherapy, the therapeutic focus has shifted away from aiming at melanoma genome stability in favor of molecularly targeted therapies. Inhibitors of the RAS/RAF/MEK/ERK (MAPK) pathway significantly slow disease progression. However, long-term clinical benefit is rare due to rapid development of drug resistance. In contrast, immune checkpoint inhibitors provide exceptionally durable responses, but only in a limited number of patients. It has been increasingly recognized that melanoma cells rely on efficient DNA repair for survival upon drug treatment, and that genome instability increases the efficacy of both MAPK inhibitors and immunotherapy. In this review, we discuss recent developments in the field of melanoma research which indicate that targeting genome stability of melanoma cells may serve as a powerful strategy to maximize the efficacy of currently available therapeutics.
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Ozbay, Tuba, and Rita Nahta. "Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines." Breast Cancer: Basic and Clinical Research 5 (January 2011): BCBCR.S7156. http://dx.doi.org/10.4137/bcbcr.s7156.
Full textAbstract:
Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation ( P < 0.05), blocked anchorage-independent growth ( P < 0.05), and induced apoptosis ( P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these drug combination studies suggested potential antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential drug antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.
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Ruscetti, Marcus, Josef Leibold, Matthew J. Bott, Myles Fennell, Amanda Kulick, Nelson R. Salgado, Chi-Chao Chen, et al. "NK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination." Science 362, no. 6421 (December 20, 2018): 1416–22. http://dx.doi.org/10.1126/science.aas9090.
Full textAbstract:
Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor–α and intercellular adhesion molecule–1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non–cell autonomous mechanisms involving NK cell surveillance.
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Voutsadakis, Ioannis A. "PI3KCA Mutations in Uterine Cervix Carcinoma." Journal of Clinical Medicine 10, no. 2 (January 10, 2021): 220. http://dx.doi.org/10.3390/jcm10020220.
Full textAbstract:
Background: Squamous cervical carcinoma represents an infection-associated malignancy that produces a high mortality when metastatic or recurrent after primary local treatment. There is an urgent need for new therapies for this cancer. Molecular lesions in cervical cancer may provide opportunities for targeted therapies development. Methods: Publicly available data from the Cancer Genome Atlas (TCGA) were analyzed to define the molecular landscape of squamous cervical carcinomas with and without mutations of PIK3CA, the gene encoding the alpha catalytic subunit of phosphatidylinositol 3 kinase (PI3K). Associations with alterations in other critical genes and pathways of cancer and the total mutation burden and copy number alteration burden of cervical cancers were examined. Results: Mutations in PIK3CA are observed in 27.1% of squamous cervical cancers. PIK3CA represents the most frequently mutated gene in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/β catenin pathway. In addition, PIK3CA mutated cervical cancers display a higher tumor mutation burden (TMB) than non-mutated cancers. Conclusion: Frequent mutations of PIK3CA gene in squamous cervical carcinomas may represent an opportunity for targeted therapies development both inhibiting the PI3K kinase and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity.
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Chung, Wei-Jen, Anneleen Daemen, Jason H. Cheng, Jason E. Long, Jonathan E. Cooper, Bu-er Wang, Christopher Tran, et al. "Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous." Proceedings of the National Academy of Sciences 114, no. 51 (December 4, 2017): E10947—E10955. http://dx.doi.org/10.1073/pnas.1708391114.
Full textAbstract:
KRAS mutant tumors are largely recalcitrant to targeted therapies. Genetically engineered mouse models (GEMMs) of Kras mutant cancer recapitulate critical aspects of this disease and are widely used for preclinical validation of targets and therapies. Through comprehensive profiling of exomes and matched transcriptomes of >200 KrasG12D-initiated GEMM tumors from one lung and two pancreatic cancer models, we discover that significant intratumoral and intertumoral genomic heterogeneity evolves during tumorigenesis. Known oncogenes and tumor suppressor genes, beyond those engineered, are mutated, amplified, and deleted. Unlike human tumors, the GEMM genomic landscapes are dominated by copy number alterations, while protein-altering mutations are rare. However, interspecies comparative analyses of the genomic landscapes demonstrate fidelity between genes altered in KRAS mutant human and murine tumors. Genes that are spontaneously altered during murine tumorigenesis are also among the most prevalent found in human indications. Using targeted therapies, we also demonstrate that this inherent tumor heterogeneity can be exploited preclinically to discover cancer-specific and genotype-specific therapeutic vulnerabilities. Focusing on Kras allelic imbalance, a feature shared by all three models, we discover that MAPK pathway inhibition impinges uniquely on this event, indicating distinct susceptibility and fitness advantage of Kras-mutant cells. These data reveal previously unknown genomic diversity among KrasG12D-initiated GEMM tumors, places them in context of human patients, and demonstrates how to exploit this inherent tumor heterogeneity to discover therapeutic vulnerabilities.
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Voutsadakis, Ioannis A. "PI3KCA Mutations in Uterine Cervix Carcinoma." Journal of Clinical Medicine 10, no. 2 (January 10, 2021): 220. http://dx.doi.org/10.3390/jcm10020220.
Full textAbstract:
Background: Squamous cervical carcinoma represents an infection-associated malignancy that produces a high mortality when metastatic or recurrent after primary local treatment. There is an urgent need for new therapies for this cancer. Molecular lesions in cervical cancer may provide opportunities for targeted therapies development. Methods: Publicly available data from the Cancer Genome Atlas (TCGA) were analyzed to define the molecular landscape of squamous cervical carcinomas with and without mutations of PIK3CA, the gene encoding the alpha catalytic subunit of phosphatidylinositol 3 kinase (PI3K). Associations with alterations in other critical genes and pathways of cancer and the total mutation burden and copy number alteration burden of cervical cancers were examined. Results: Mutations in PIK3CA are observed in 27.1% of squamous cervical cancers. PIK3CA represents the most frequently mutated gene in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/β catenin pathway. In addition, PIK3CA mutated cervical cancers display a higher tumor mutation burden (TMB) than non-mutated cancers. Conclusion: Frequent mutations of PIK3CA gene in squamous cervical carcinomas may represent an opportunity for targeted therapies development both inhibiting the PI3K kinase and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity.