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

Prashanthi Ramesh, Simone di Franco, Lidia Atencia Taboada, Le Zhang, Annalisa Nicotra, Giorgio Stassi, Jan Paul Medema

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4 Citations (Scopus)


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.
Original languageEnglish
Article number110374
JournalCell reports
Issue number7
Publication statusPublished - 15 Feb 2022


  • BCL-XL
  • BH3 mimetics
  • FGFR4
  • MCL-1
  • colorectal cancer
  • resistance
  • stem cells

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