Bet Bromodomain Proteins Regulate The Canonical Wnt Signaling And Drug Resistance In Colorectal Cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAThe canonical WNT signaling is aberrantly activated in the vast majority of colorectal cancer (CRC) and results in activation of beta-catenin and its downstream target MYC. These two oncogenic transcription factors play central roles in CRC pathogenesis, but are refractory to direct pharmacological interventions. The recurrent mutations of APC or β-catenin in CRC also limit the utilities of currently available WNT inhibitors that mostly target upstream regulators. The bromodomain and extra-terminal domain (BET) family epigenetic readers recently emerged as a key regulator of MYC expression. In the present study, we demonstrated that BET proteins regulated beta-catenin-mediated MYC expression in CRC. Inhibition of BET proteins repressed activities of both wild type and constitutively active β-catenin mutants. Pharmacological or genetic targeting of BET proteins broadly impaired proliferation and survival in CRC cells, including KRAS or BRAF-mutant lines. Furthermore, BET bromodomain inhibitors synergistically sensitized CRC cells to inhibitors of the MAPK pathway. The ability of BET inhibitors to augment the efficacy of the MAPK pathway inhibitors is potentially secondary to altered balance among pro-survival and pro-apoptotic regulators. Using KRAS- or BRAF-mutant CRC xenograft models, we showed that a combination of BET inhibitor and MEK inhibitor, but not either agent alone, induced significant tumor regression. Our findings suggest that BET-based epigenetic therapy can be utilized as an alternative approach to block the canonical WNT signaling in CRC and potentially other human cancers, in particular those carrying APC or beta-catenin mutations. Our results also identify a novel combination therapy for treating CRCs, including those refractory to currently available therapeutic options.Citation Format: Lihong Wang, Yufang Ma, Ethan Lee, Jialiang Wang. BET bromodomain proteins regulate the canonical WNT signaling and drug resistance in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3529. doi:10.1158/1538-7445.AM2015-3529