Abstract LB-124: COP1 E3 ligase modulates response to oncogenic MAPK pathway inhibition
| Autor: | Manasi K. Mayekar, Trever Bivona |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:LB-124 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Oncogenic activation of the RAS-MAPK pathway is the underlying cause of the majority of lung adenocarcinomas. In these tumors, RAS-MAPK pathway activation occurs via diverse genetic alterations in upstream receptor tyrosine kinases such as EGFR and ALK as well as in RAS, BRAF, MEK and RAS GTPase activating protein (GAP) and tumor suppressor, NF1. Therapies targeting components of the RAS-MAPK pathway can lead to initial tumor responses in many patients. But most patients show only a partial response and many do not respond at all despite the presence of a RAS-MAPK pathway-activating genetic lesion in the tumor. Hence, it is critical to understand the molecular basis of response and resistance to targeted therapies acting against the RAS-MAPK pathway in lung adenocarcinomas in order to improve patient survival. We conducted a genetic screen to identify modifiers of response to MAPK pathway inhibition in lung cancer. Our genetic screen uncovered the E3 ubiquitin ligase COP1/RFWD2 as a novel genetic modifier. We found that depletion of COP1 and members of its complex, as well proteasomal subunits, confers resistance to RAS-MAPK pathway inhibition in human lung adenocarcinoma cells with oncogenically-activated MAPK pathway. Since two critical MAPK pathway effectors c-Jun and ETV1 have been shown to be targets of COP1 E3 ligase complex-mediated proteosomal degradation, we tested if depletion of COP1 alters the levels of phosphorylated c-Jun and ETV1. Intriguingly, we did not observe a substantial impact of COP1 depletion on the levels of these effectors. Based on these observations, we hypothesize that depletion of COP1 confers resistance to MAPK pathway inhibition in RAS-MAPK pathway driven lung adenocarcinomas through accumulation of a novel protein substrate(s) that allows the survival and/or proliferation of these cells upon MAPK pathway inhibition. We will uncover the mechanism of resistance by identifying this substrate(s) of COP1 whose accumulation facilitates cell survival and/or proliferation upon MAPK pathway inhibition. This work will improve our understanding of the molecular basis of tumor cell resilience during initial treatment as well as of primary treatment resistance. Additionally, it could lead to identification of a novel biomarker for predicting response to MAPK pathway inhibitor therapy and a therapeutic target(s) that could be co-targeted with MAPK pathway signaling to improve the patient response in MAPK pathway driven lung adenocarcinomas. Citation Format: Manasi K. Mayekar, Trever Bivona. COP1 E3 ligase modulates response to oncogenic MAPK pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-124. doi:10.1158/1538-7445.AM2017-LB-124 |
| Databáze: | OpenAIRE |
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