RRC ID 79009
Author Wu Q, Zhen Y, Shi L, Vu P, Greninger P, Adil R, Merritt J, Egan R, Wu MJ, Yin X, Ferrone CR, Deshpande V, Baiev I, Pinto CJ, McLoughlin DE, Walmsley CS, Stone JR, Gordan JD, Zhu AX, Juric D, Goyal L, Benes CH, Bardeesy N.
Title EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma.
Journal Cancer Discov
Abstract UNLABELLED:FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma.
SIGNIFICANCE:We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.
Volume 12(5)
Pages 1378-1395
Published 2022-5-2
DOI 10.1158/2159-8290.CD-21-1168
PII 694422
PMID 35420673
PMC PMC9064956
MeSH Bile Duct Neoplasms* / drug therapy Bile Duct Neoplasms* / genetics Bile Duct Neoplasms* / metabolism Bile Ducts, Intrahepatic / metabolism Bile Ducts, Intrahepatic / pathology Cholangiocarcinoma* / drug therapy Cholangiocarcinoma* / genetics Cholangiocarcinoma* / metabolism ErbB Receptors / genetics Humans Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use Pyrimidines / pharmacology Receptor, Fibroblast Growth Factor, Type 2 / genetics Receptor, Fibroblast Growth Factor, Type 2 / metabolism
Human and Animal Cells RBE(RCB1292)