Kinase Fusions Drive Endocrine Resistance In Estrogen Receptor-Positive Breast Cancer

Abstract Oncogenic kinase activation by gene fusions can promote cancer development and tumor progression, however, kinase fusions have not been characterized extensively in breast cancer. In this study, we characterized kinase fusions in a large cohort of 4854 breast cancer patients using clinical DNA and/or RNA next generation sequencing platforms. Twenty-seven cases harboring kinase fusions were identified, including 11 FGFR (5 FGFR2, 3 FGFR3, 3 FGFR1), 5 BRAF, 4 NTRK1, 2 RET, 2 ROS1, 1 ALK, 1 ERBB2, and 1 MET. Eight patients with a history of endocrine therapy had available pre-treatment samples, of which six were negative for kinase fusion, and ESR1 hotspot mutations were not observed in any of these kinase fusion-positive samples. These findings suggest a potential role for kinase fusions in endocrine therapy resistance and prompted us to model the kinase fusions in human breast cancer cell lines. Ectopic expression of LMNA-NTRK1 fusion kinase activated growth factor signaling cascades, including PI3K-AKT and MAPK-ERK pathways, and promoted hormone-independent growth in MCF7 and T47D cells. Enforced expression of the LMNA-NTRK1 fusion conferred resistance to the ER antagonist fulvestrant and combined treatment of fulvestrant and the Trk inhibitor larotrectinib completely blocked the growth of LMNA-NTRK+ breast cancer cells. Similarly, expression of the EML4-ALK fusion also activated growth factor signaling pathways and caused resistance to estrogen depletion and induced sensitivity to the ALK inhibitor, Ceritinib. Treatment of xenografted LMNA-NTRK1 expressing tumors confirmed the efficacy of the combined treatment of antiestrogen and NTRK1 inhibition in vivo. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit. Overall, our findings demonstrate that kinase fusions promote endocrine resistance in ER-positive breast cancer, and suggest that fusion screening in advanced breast cancer, particularly those with ER-positive breast cancer at progression on hormone therapy can identify rare tumors harboring targetable kinase fusions. Citation Format: Bo Liu, Dara S. Ross, Alison M. Schram, Pedram Razavi, Stephen M. Lagana, Yanming Zhang, Maurizio Scaltriti, Jacqueline F. Bromberg, Marc Ladanyi, David M. Hyman, Alexander Drilon, Ahmet Zahir, Ryma Benayed, Jaclyn F. Hechtman, Sarat Chandarlapaty. Kinase fusions drive endocrine resistance in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5280.