Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer
2019
Using an ORF
kinomescreen in MCF-7 cells treated with the CDK4/6 inhibitor
ribociclibplus
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 ±
ribociclibor
palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI
erdafitinibto
palbociclib/
fulvestrantinduced 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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