{"doi":"10.1158/1078-0432.ccr-19-3958","title":"Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer","abstract":"<h4>Purpose</h4>To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER<sup>+</sup> breast cancer.<h4>Experimental design</h4>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<sup>+</sup> 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.<h4>Results</h4>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 <i>FGFR1, FGFR2</i>, or <i>FGF3</i> amplifications or <i>FGFR2</i> 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. <i>In vitro</i> experiments in ER<sup>+</sup> 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.<h4>Conclusions</h4>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.","journal":"Clinical Cancer Research","year":2020,"id":4778,"datarank":0.7312795984801728,"base_score":4.875197323201151,"endowment":4.875197323201151,"self_citation_contribution":0.7312795984801728,"citation_network_contribution":0.0,"self_endowment_contribution":0.7312795984801728,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":130,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0876,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-11-13","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":3739,"name":"Ofir Cohen","orcid":"0000-0002-0043-6838","position":1,"is_corresponding":false},{"id":3740,"name":"Kailey J. Kowalski","orcid":null,"position":2,"is_corresponding":false},{"id":3741,"name":"Justin G. Kusiel","orcid":null,"position":3,"is_corresponding":false},{"id":3742,"name":"Jorge E. Buendia-Buendia","orcid":"0000-0002-9675-6827","position":4,"is_corresponding":false},{"id":3743,"name":"Michael S. Cuoco","orcid":"0000-0003-2163-5120","position":5,"is_corresponding":false},{"id":3744,"name":"Pedro Exman","orcid":null,"position":6,"is_corresponding":false},{"id":3745,"name":"Seth A. Wander","orcid":"0000-0002-4127-4708","position":7,"is_corresponding":false},{"id":3746,"name":"Adrienne G. Waks","orcid":"0000-0001-5649-7229","position":8,"is_corresponding":false},{"id":3747,"name":"Utthara Nayar","orcid":"0000-0002-9024-6084","position":9,"is_corresponding":false},{"id":3748,"name":"Jon Chung","orcid":"0000-0003-0526-3670","position":10,"is_corresponding":false},{"id":3749,"name":"Samuel S. Freeman","orcid":"0000-0001-8285-0057","position":11,"is_corresponding":false},{"id":1272,"name":"Vincent A. Miller","orcid":"0000-0003-1667-3771","position":13,"is_corresponding":false},{"id":3750,"name":"Federica Piccioni","orcid":"0000-0003-1210-3210","position":14,"is_corresponding":false},{"id":3751,"name":"David E. Root","orcid":"0000-0001-5122-861X","position":15,"is_corresponding":false},{"id":29633,"name":"Prisca Liberali","orcid":"0000-0003-0695-6081","position":16,"is_corresponding":false},{"id":3752,"name":"Eric P. Winer","orcid":"0000-0002-8819-1723","position":17,"is_corresponding":false},{"id":3753,"name":"Nancy U. Lin","orcid":"0000-0003-2263-5413","position":18,"is_corresponding":false},{"id":3754,"name":"Nikhil Wagle","orcid":"0000-0003-3332-9438","position":19,"is_corresponding":false},{"id":2697,"name":"Orit Rozenblatt–Rosen","orcid":"0000-0001-6313-3570","position":20,"is_corresponding":false},{"id":3738,"name":"Pingping Mao","orcid":null,"position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}