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Clin Cancer Res DOI:10.1158/1078-0432.CCR-19-3958

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

Publication TypeJournal Article
Year of Publication2020
AuthorsMao, P, Cohen, O, Kowalski, KJ, Kusiel, JG, Buendia-Buendia, JE, Cuoco, MS, Exman, P, Wander, SA, Waks, AG, Nayar, U, Chung, J, Freeman, S, Rozenblatt-Rosen, O, Miller, VA, Piccioni, F, Root, DE, Regev, A, Winer, EP, Lin, NU, Wagle, N
JournalClin Cancer Res
Volume26
Issue22
Pages5974-5989
Date Published2020 Nov 15
ISSN1557-3265
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 , or amplifications or 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. 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.

DOI10.1158/1078-0432.CCR-19-3958
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32723837?dopt=Abstract

Alternate JournalClin Cancer Res
PubMed ID32723837