Acquired FGFR and FGF alterations confer resistance to Estrogen Receptor (ER) targeted therapy in ERþ metastatic breast cancer

Pingping Mao, Ofir Cohen, Kailey J. Kowalski, Justin G. Kusiel, Jorge E. Buendia-Buendia, Michael S. Cuoco, Pedro Exman, Seth A. Wander, Adrienne G. Waks, Utthara Nayar, Jon Chung, Samuel Freeman, Orit Rozenblatt-Rosen, Vincent A. Miller, Federica Piccioni, David E. Root, Aviv Regev, Eric P. Winer, Nancy U. Lin, Nikhil Wagle

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To identify clinically relevant mechanisms of resistance to ER-directed therapies in ERþ breast cancer. Experimental Design: We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. In parallel, we performed whole-exome sequencing in paired pretreatment and postresistance biopsies from 60 patients with ERþ metastatic breast cancer who had developed resistance to ER-targeted therapy. Furthermore, we performed experiments to validate resistance genes/pathways and to identify drug combinations to overcome resistance. Results: Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3 amplifications or FGFR2 mutations in 24 (40%) of the postresistance biopsies. In 12 of the 24 postresistance tumors exhibiting FGFR/FGF alterations, these alterations were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ERþ breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib. RNA sequencing of resistant cell lines demonstrated that FGFR/FGF induced resistance through ER reprogramming and activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors, a MEK inhibitor, and/or a SHP2 inhibitor. Conclusions: Our results suggest that FGFR pathway is a distinct mechanism of acquired resistance to ER-directed therapy that can be overcome by FGFR and/or MAPK pathway inhibitors.

Original languageEnglish (US)
Pages (from-to)5974-5989
Number of pages16
JournalClinical Cancer Research
Volume26
Issue number22
DOIs
StatePublished - Nov 15 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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