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BCL-XL inhibition induces an FGFR4 mediated rescue response in colorectal cancer

ABSTRACT: The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3-mimetics can induce apoptosis. To identify pathways that can regulate sensitivity to BCL-XL inhibition, we screened a compound library for synergy with low dose BCL-XL inhibitor A-1155463 and reveal that FGFR4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159504 | GEO | 2021/12/22

REPOSITORIES: GEO

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BCL-XL inhibition induces an FGFR4 mediated rescue response in colorectal cancer

Project description:BCL-XL inhibition induces an FGFR4 mediated rescue response in colorectal cancer

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