Ethan Lee
Faculty Member
Last active: 7/23/2019

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.

Ma Y, Wang L, Neitzel LR, Loganathan SN, Tang N, Qin L, Crispi EE, Guo Y, Knapp S, Beauchamp RD, Lee E, Wang J
Clin Cancer Res. 2017 23 (8): 2027-2037

PMID: 27678457 · PMCID: PMC5368030 · DOI:10.1158/1078-0432.CCR-16-0453

The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer. Using a panel of molecularly defined colorectal cancer cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches. BET inhibitors as monotherapy moderately reduced colorectal cancer cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized colorectal cancer cells to BET inhibitors, leading to potent apoptosis and MYC downregulation and A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous colorectal cancer xenografts. Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in colorectal cancer and propose an effective combination strategy for the treatment of colorectal cancer. .

©2016 American Association for Cancer Research.

MeSH Terms (17)

Animals Antineoplastic Agents Apoptosis Cell Line, Tumor Cell Proliferation Colorectal Neoplasms Drug Resistance, Neoplasm Female Gene Expression Regulation, Neoplastic Humans MAP Kinase Signaling System Mice Mice, Nude Nuclear Proteins Real-Time Polymerase Chain Reaction Transcription Factors Xenograft Model Antitumor Assays

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