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.