@article{c43c4615d0944e80bc5b84dcf861cb0d,
title = "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. 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.",
keywords = "BCL-XL, BH3 mimetics, FGFR4, MCL-1, colorectal cancer, resistance, stem cells",
author = "Prashanthi Ramesh and {di Franco}, Simone and {Atencia Taboada}, Lidia and Le Zhang and Annalisa Nicotra and Giorgio Stassi and Medema, {Jan Paul}",
note = "Funding Information: Supported by Oncode , KWF project 2015–7587 and 10150 . L.Z. was supported by a CSC scholarship. G.S. is supported by AIRC 5x1000 #9979 , AIRC IG 21445 , and PRIN 2017WNKSLR grants. The authors would like to thank the laboratory of Xu Luo at the University of Nebraska Medical Center for kindly providing the HCT116 OctaKO cell line. The authors would also like to thank Ferry de Klein for assistance with the drug dispensing robot. Funding Information: Supported by Oncode, KWF project 2015?7587 and 10150. L.Z. was supported by a CSC scholarship. G.S. is supported by AIRC 5x1000 #9979, AIRC IG 21445, and PRIN 2017WNKSLR grants. The authors would like to thank the laboratory of Xu Luo at the University of Nebraska Medical Center for kindly providing the HCT116 OctaKO cell line. The authors would also like to thank Ferry de Klein for assistance with the drug dispensing robot. Conception and design of the study: P.R. and J.P.M. Experimental work: P.R. S.F. L.A.T. L.Z. and A.N. Data analysis and interpretation: P.R. S.F. and J.P.M. Drafting of the manuscript: P.R, J.P.M. Final manuscript contribution: P.R. S.F. L.A.T. L.Z. A.N. G.S. and J.P.M. J.P.M. serves as an advisor to AbbVie on their colorectal cancer program. All other authors declare no potential competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = feb,
day = "15",
doi = "https://doi.org/10.1016/j.celrep.2022.110374",
language = "English",
volume = "38",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}