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. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 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.

Ramesh, P., Di Franco, S., Atencia Taboada, L., Zhang, L.e., Nicotra, A., Stassi, G., et al. (2022). BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer. CELL REPORTS, 38(7) [10.1016/j.celrep.2022.110374].

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

Di Franco, Simone;Nicotra, Annalisa;Stassi, Giorgio;
2022-02-15

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. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 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.
https://www.cell.com/cell-reports/pdfExtended/S2211-1247(22)00095-X
Ramesh, P., Di Franco, S., Atencia Taboada, L., Zhang, L.e., Nicotra, A., Stassi, G., et al. (2022). BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer. CELL REPORTS, 38(7) [10.1016/j.celrep.2022.110374].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/535358
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