Epigenetic regulation of targeted therapy resistance in human melanoma by the CoREST complex
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Abstract
Melanoma, the fifth most common cancer in the United States, originates from melanocytes, UV protective cells in the skin. Despite advancements in treatment options for patients with melanoma, resistance to therapy remains a significant obstacle to long term efficacy. Current treatments, targeting driver mutations in the MAPK pathway (MAPKi), often leads to patient relapse within one year due to a subset of drug tolerant persister cells (DTPs), whose survival is thought to be driven by epigenetic tumor cell plasticity. We have investigated the CoREST chromatin remodeling complex in melanoma, uncovering its role in facilitating tumor cell plasticity. We hypothesize that these epigenetic modifications by CoREST are pivotal in enabling DTPs to adapt and survive in hostile environments, such as those encountered during targeted cancer therapy. In collaboration with Dr. Philip Cole’s laboratory at Harvard Medical School, we developed a novel CoREST inhibitor corin, that inhibits its enzymatic activity. To address this hypothesis, we propose an integrated experimental approach that emphasizes both in vitro cell culture studies and in-depth physiological studies using an in vivo model, utilizing MAPKi treatment combined with CoREST inhibition. Our preliminary data indicates that this combination significantly reduces tumor cell proliferation, colony formation, and the development of DTP cells in half of the melanoma cell lines tested. Additionally, treatment with corin, alone and in combination with MAPKi, increased histone marks H3K4me2 and H4K9ac, suggesting its potential as a dual-action therapeutic strategy targeting both epigenetic and cellular aspects of melanoma. Anticipated findings will provide valuable insights into the epigenetic changes occurring within the tumor microenvironment in response to our treatment regimen and may yield a deeper understanding of how CoREST inhibition, particularly with corin, impacts the epigenetic landscape of melanoma cells in a physiologically relevant setting.
Description
2024