EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion–Positive Cholangiocarcinoma
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 25, 2022
- Source ID
- 10.1158/2159-8290.cd-21-1168
Entities
People
- Andrew X Zhu
- Charlotte S. Walmsley
- Christopher J. Pinto
- Cristina R. Ferrone
- Cyril H. Benes
- Daniel E. McLoughlin
- Dejan Juric
- Islam Baiev
- James R. Stone
- John D Gordan
- Joshua Merritt
- Lei Shi
- Lipika Goyal
- Meng-ju Wu
- Nabeel Bardeesy
- Patricia Greninger
- Phuong Vu
- Qibiao Wu
- Ramzi Adil
- Regina Egan
- Vikram Deshpande
- Xunqin Yin
- Yuanli Zhen
Organizations
- Harvard Medical School
- National Institutes of Health
- United States Department of Defense
- University of California, San Francisco
- Wellcome