Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Homo sapiens

We expressed 559 kinase open reading frames (ORFs) in ER+ MCF-7 cells treated with fulvestrant ? the CDK4/6 inhibitor ribociclib. Eleven kinases induced a >30% increase in viability in cells treated with this combination and five of these (FGFR1, FRK, HCK, FGR, CRKL) also induced resistance in secondary screens. FGFR1-amplified ER+ breast cancer cells as well as MCF-7 and T47D cells transduced with FGFR1 were less sensitive to fulvestrant ? ribociclib or palbociclib. This effect was abrogated by addition of the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Treatment with fulvestrant, palbociclib or both delayed growth of FGFR1-amplified ER+ patient-derived xenografts (PDXs). Addition of the FGFR specific TKI erdafitinib to fulvestrant/palbociclib resulted in complete responses without associated toxicity. Treatment of FGFR1-amplified cells with FGF2 strongly induced a CCND1 (cyclin D1) gene expression signature. Downregulation of CCND1 with siRNA increased the sensitivity of FGFR1-amplified cells to fulvestrant/palbociclib, thus phenocopying the effect of FGFR TKIs. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients pre- and post-progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA analysis in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibit a progression free survival of 10.61 months vs. 24.84 months in patients with wild type FGFR1. In sum, aberrant FGFR signaling reduces the antitumor effect of CDK4/6 inhibitors in combination with antiestrogens. Thus, breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.