Data from: Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer

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.RNAseq CAMA1RNA-seq CAMA1Final ReportCell cycle array Fig. 5Afinal_report.xlsCCND1CCND1 quantification by PCR Fig. 5Bccnd1.xlsNanostring analysis in PDX modelNanostring analysis in PDX modelNanostring Fig6D.csvFigure 7ActDNA analysis in Fig. 7asanitized_vcf.zipFigure 7B Figure 7CFGFR1_NatureComm.zipFunding provided by: National Science FoundationCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000001Award Number: This study was supported by NIH Breast SPORE grant P50 CA098131, Vanderbilt-Ingram Cancer Center Support grant P30 CA68485, Susan G. Komen for the Cure Breast Cancer Foundation grant SAC100013, and a grant from the Breast Cancer Research Foundation. L.F. was supported by Italian Association of Medical Oncology. V.M. Jansen was supported by Conquer Cancer Foundation ASCO Young Investigator Award 8364, Susan G. Komen Postdoctoral Fellowship Grant PDF15329319 and the Vanderbilt Clinical Oncology Research Career Development Program (2K12CA090625-17). J.A. Bauer was supported by NCI Research Specialist Award R50 CA21120