Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States with an estimated 52,550 deaths in 2023. Approximately, 5-10% of metastatic colorectal cancer (mCRC) patients have BRAF mutations, which is associated with extremely poor prognosis and dismal survival. BRAFV600E-mutated CRC harbors significant epigenetic mutations; however, the role of epigenome in tumor progression and utilization of epigenetic drugs in these patients are not yet understood. Evaluation of specific epigenetic proteins could be targets for therapy in these cancers revealed BRD2 as an epigenetic marker that may sensitize cell lines to BRAF and EGFR inhibitor. Moreover, our prelimi...

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Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States with an estimated 52,550 deaths in 2023. Approximately, 5-10% of metastatic colorectal cancer (mCRC) patients have BRAF mutations, which is associated with extremely poor prognosis and dismal survival. BRAFV600E-mutated CRC harbors significant epigenetic mutations; however, the role of epigenome in tumor progression and utilization of epigenetic drugs in these patients are not yet understood. Evaluation of specific epigenetic proteins could be targets for therapy in these cancers revealed BRD2 as an epigenetic marker that may sensitize cell lines to BRAF and EGFR inhibitor. Moreover, our preliminary studies in colorectal PDX models showed impressive tumor regression with bromodomain (BRD) inhibitor, ZEN-3694, in combination with the BRAFi/EGFRi. Hence, we hypothesize that, epigenetic reprogramming of the tumor and immune cells in response to BRAFi/anti-EGFR combination could be targeted with BRD inhibitors to improve response rates in BRAF-mutant colorectal cancers. The objectives of this proposal are to 1) determine the tumor-intrinsic mechanisms of response to BRAFi/anti-EGFR with or without BRD inhibition in CRC, 2) determine the tumor extrinsic mechanisms of response to BRAFi/anti-EGFR therapy in combination with BRD inhibitors or immune checkpoint therapy (ICB), and determine the epigenetic mechanism of response to BRAFi/anti-EGFR +/- BETi and test combination therapy with DNA methyltransferase transferase (DNMTi). Our study will not only have a significant impact on understanding the mechanistic insights into the molecular and cellular states of the immune and tumor cells that associate with response/resistance to BRAFi/anti-EGFR treatment, but also provide proof-of-concept experiments for next generation combination therapy strategies with epigenetic agents.

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