Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER + Metastatic Breast Cancer

Clin Cancer Res. 2020 Nov 15;26(22):5974-5989. doi: 10.1158/1078-0432.CCR-19-3958. Epub 2020 Jul 28.

Abstract

Purpose: To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER+ 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 ER+ 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 ER+ 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Fibroblast Growth Factor 3 / genetics*
  • Fulvestrant / administration & dosage
  • Fulvestrant / adverse effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MCF-7 Cells
  • Middle Aged
  • Mutation / genetics
  • Neoplasm Metastasis
  • Piperazines / administration & dosage
  • Piperazines / adverse effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • Receptors, Estrogen / genetics
  • Whole Exome Sequencing
  • Xenograft Model Antitumor Assays

Substances

  • FGF3 protein, human
  • Fibroblast Growth Factor 3
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Receptors, Estrogen
  • Fulvestrant
  • FGFR1 protein, human
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2
  • palbociclib