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

被引:98
|
作者
Mao, Pingping [1 ,2 ,3 ,4 ]
Cohen, Ofir [1 ,2 ,3 ,4 ]
Kowalski, Kailey J. [1 ,2 ,3 ,4 ]
Kusiel, Justin G. [1 ,2 ,3 ,4 ]
Buendia-Buendia, Jorge E. [1 ,2 ,3 ,4 ]
Cuoco, Michael S. [5 ]
Exman, Pedro [2 ]
Wander, Seth A. [1 ,2 ,3 ,4 ,6 ]
Waks, Adrienne G. [1 ,2 ,3 ,4 ,6 ]
Nayar, Utthara [1 ,2 ,3 ,4 ]
Chung, Jon [7 ]
Freeman, Samuel [4 ]
Rozenblatt-Rosen, Orit [5 ]
Miller, Vincent A. [7 ]
Piccioni, Federica [4 ]
Root, David E. [4 ]
Regev, Aviv [5 ,8 ,9 ,10 ]
Winer, Eric P. [2 ,3 ,6 ]
Lin, Nancy U. [2 ,3 ,6 ]
Wagle, Nikhil [1 ,2 ,3 ,4 ,6 ]
机构
[1] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA
[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
[3] Harvard Med Sch, Boston, MA 02115 USA
[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA
[5] Broad Inst MIT & Harvard, Klarman Cell Observ, Cambridge, MA 02142 USA
[6] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA
[7] Fdn Med Inc, Cambridge, MA USA
[8] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA
[9] MIT, Dept Biol, Koch Inst Integrat Canc Res, Cambridge, MA USA
[10] Genentech Inc, San Francisco, CA 94080 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
GROWTH-FACTOR RECEPTORS; ENDOCRINE RESISTANCE; ESR1; MUTATIONS; KINASE; INHIBITION; MECHANISM; SCREEN; LANDSCAPE; DOVITINIB; TAMOXIFEN;
D O I
10.1158/1078-0432.CCR-19-3958
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 degra-ders. 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.
引用
收藏
页码:5974 / 5989
页数:16
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