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Ref Type Journal Article
PMID (32723837)
Authors Mao 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
Title Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 22
Date 2020 11 15
URL
Abstract Text To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER+ breast cancer.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
FIIN-3 FIIN-3 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
FIIN-3 FIIN3|FIIN 3 FGFR Inhibitor (Pan) 24 FIIN-3 is a selective, irreversible FGFR inhibitor with activity against FGFR2 gatekeeper mutations, which potentially results in decreased tumor cell proliferation (PMID: 25349422, PMID: 32723837).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 M538I missense gain of function FGFR2 M538I (corresponds to M537I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). M538I confers a gain of function to the Fgfr2 protein as demonstrated by increased Fgfr2 kinase activity (PMID: 32723837, PMID: 23908597) and enhanced cell proliferation in the presence of ligand in cell culture (PMID: 23908597), and has been associated with decreased sensitivity to some FGFR inhibitors (PMID: 23908597).
FGFR2 N550K missense gain of function FGFR2 N550K (corresponds to N549K in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550K results in increased Fgfr2 kinase activity (PMID: 32723837, PMID: 23908597) and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 K660N estrogen-receptor positive breast cancer sensitive FIIN-3 Preclinical - Cell culture Actionable In a preclinical study, FIIN-3 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 K660N in culture (PMID: 32723837). 32723837
FGFR2 K660N breast cancer sensitive AZD4547 + Fulvestrant Preclinical - Cell culture Actionable In a preclinical study, AZD4547 and Faslodex (fulvestrant) combination treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 K660N in culture (PMID: 32723837). 32723837
FGFR2 N550K estrogen-receptor positive breast cancer sensitive FIIN-3 Preclinical - Cell culture Actionable In a preclinical study, FIIN-3 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 N550K in culture (PMID: 32723837). 32723837
FGFR2 K660N estrogen-receptor positive breast cancer sensitive SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 K660N in culture (PMID: 32723837). 32723837
FGFR2 K660N estrogen-receptor positive breast cancer sensitive FIIN-2 Preclinical - Cell culture Actionable In a preclinical study, FIIN-2 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 K660N in culture (PMID: 32723837). 32723837
FGFR2 M538I estrogen-receptor positive breast cancer sensitive SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). 32723837
FGFR2 M538I estrogen-receptor positive breast cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). 32723837
FGFR2 M538I estrogen-receptor positive breast cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). 32723837
FGFR2 N550K estrogen-receptor positive breast cancer sensitive SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 N550K in culture (PMID: 32723837). 32723837
FGFR2 K660N estrogen-receptor positive breast cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 K660N in culture (PMID: 32723837). 32723837
FGFR2 M538I estrogen-receptor positive breast cancer sensitive FIIN-2 Preclinical - Cell culture Actionable In a preclinical study, FIIN-2 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). 32723837
FGFR2 M538I breast cancer sensitive FIIN-3 + Fulvestrant Preclinical - Cell culture Actionable In a preclinical study, Faslodex (fulvestrant) and FIIN-3 combination treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). 32723837
FGFR2 N550K estrogen-receptor positive breast cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 N550K in culture (PMID: 32723837). 32723837
FGFR2 K660N estrogen-receptor positive breast cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 K660N in culture (PMID: 32723837). 32723837
FGFR2 N550K estrogen-receptor positive breast cancer sensitive FIIN-2 Preclinical - Cell culture Actionable In a preclinical study, FIIN-2 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 N550K in culture (PMID: 32723837). 32723837
FGFR2 N550K estrogen-receptor positive breast cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 N550K in culture (PMID: 32723837). 32723837
FGFR2 M538I estrogen-receptor positive breast cancer sensitive FIIN-3 Preclinical - Cell culture Actionable In a preclinical study, FIIN-3 treatment decreased viability of ESR1-positive breast cancer cells expressing FGFR2 M538I in culture (PMID: 32723837). 32723837