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RESEARCH PRODUCT
BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer
Prashanthi RameshSimone Di FrancoLidia Atencia TaboadaLe ZhangAnnalisa NicotraGiorgio StassiJan Paul Medemasubject
MaleBH3 mimeticsIndolesAxitinibColonDrug Evaluation Preclinicalbcl-X Proteincolorectal cancerMice SCIDGeneral Biochemistry Genetics and Molecular BiologyresistanceMice Inbred NODstem cellsCell Line TumorBCL-XLBCL-XL FGFR4 colorectal cancer apoptosis.AnimalsHumansReceptor Fibroblast Growth Factor Type 4BenzothiazolesAgedCell DeathDrug SynergismMiddle AgedIsoquinolinesOrganoidsNeoplastic Stem CellsFGFR4FemaleMCL-1Colorectal Neoplasmsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2022-02-15 | Cell reports |