Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09068-2
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Funding
- NIH Breast SPORE grant [P50 CA098131]
- Vanderbilt-Ingram Cancer Center Support grant [P30 CA68485]
- Susan G. Komen for the Cure Breast Cancer Foundation [SAC100013]
- Breast Cancer Research Foundation
- Conquer Cancer Foundation ASCO Young Investigator Award [8364]
- Susan G. Komen Postdoctoral Fellowship [PDF15329319]
- Vanderbilt Clinical Oncology Research Career Development Program [2K12CA090625-17]
- NCI Research Specialist Award [R50 CA211206]
- AIRC under MFAG [21505]
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Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant +/- ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
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