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

Abstract

Purpose 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 (CRC). Experimental Design Using a panel of molecularly defined CRC 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. Results BET inhibitors as monotherapy moderately reduced CRC cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized CRC cells to BET inhibitors, leading to potent apoptosis and MYC downregulation in vitro and in vivo. A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous CRC xenografts. Conclusions Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in CRC and propose an effective combination strategy for the treatment of CRC.

FBXW4 Acts as a Protector of FOLFOX-Based Chemotherapy in Metastatic Colorectal Cancer Identified by Co-Expression Network Analysis

“…The results from the WGCNA demonstrated that the black module is the hub module, and that the genes in the black module were enriched for cell proliferation, the MAPK signaling pathway, and the PI3K signaling pathway, which has already been reported to be associated with resistance to multiple chemotherapy regimens in cancers. These findings were similar to observations reported in our previous study (Russo et al, 2009;Arqués et al, 2016;Ma et al, 2017;Zhang et al, 2018). These results are in accordance with our previous study (Russo et al, 2009;Arqués et al, 2016;Ma et al, 2017;Zhang et al, 2018).…”

“…These findings were similar to observations reported in our previous study (Russo et al, 2009;Arqués et al, 2016;Ma et al, 2017;Zhang et al, 2018). These results are in accordance with our previous study (Russo et al, 2009;Arqués et al, 2016;Ma et al, 2017;Zhang et al, 2018). Thus, the black module was significantly associated with FOLFOX-resistance.…”

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

“…Importantly, the same concept proved successful in mutant NRAS-driven malignant melanoma, where BRD4 and MEK inhibitors synergized to inhibit tumor growth in mouse melanoma models [196]. Combinatorial treatment with MAPK and BET inhibitors also could overcome intrinsic MAPK inhibitor resistance in colorectal cancer models [198]. Overall, the BET family of epigenetic regulators has emerged as promising therapeutic targets in MAPK mutated cancers and a number of small molecule inhibitors of BET proteins have been developed or undergoing clinical investigation.…”

Induction of MNK Kinase–dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors

“…In contrast, ovarian cancer cells activate compensatory prosurvival kinase network to overcome the effects of BETis (38). Also, colorectal cancer cells with intrinsic resistance to BETis have increased activation of the MEK/ERK signaling pathway (39). In this report, we show that cancer cells demonstrate increased MNK and eIF4E phosphorylation following treatment with BETis JQ1 and OTX015 as a compensatory prosurvival feedback mechanism to limit the antiproliferative effects of BETis.…”