Abstract
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.
Highlights
Using an open reading frame (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
Presence of FGFR1 alterations in baseline plasma tumor DNA was associated with a shorter progression free survival in the large randomized MONALEESA-2 trial of letrozole ± ribociclib, suggesting aberrant FGFR signaling is a potential mechanism of escape from endocrine therapy plus CDK4/6 inhibitors, a current standard of care in advanced estrogen receptor (ER)+ breast cancer
To validate the 17 ORFs identified in the fulvestrant plus ribociclib screen, we transfected each of these kinases into MCF-7 cells and treated them with fulvestrant plus ribociclib and fulvestrant plus palbociclib over a range of drug concentrations
Summary
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. The addition of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib to aromatase inhibitors or to the ER downregulator fulvestrant have resulted in a markedly improved progression-free survival compared to the antiestrogen alone in patients with advanced ER + breast cancer[6,7,8,9,10], leading to their approval by the FDA. To discover mechanisms of acquired resistance to antiestrogens plus CDK4/6 inhibitors, we expressed a library of 559 sequencevalidated kinase open reading frame (ORF) clones[11] in ER+ MCF-7 cells treated with fulvestrant ± ribociclib and found that FGFR1 overexpression induces less sensitivity to this combination. Presence of FGFR1 alterations in baseline plasma tumor DNA was associated with a shorter progression free survival in the large randomized MONALEESA-2 trial of letrozole ± ribociclib, suggesting aberrant FGFR signaling is a potential mechanism of escape from endocrine therapy plus CDK4/6 inhibitors, a current standard of care in advanced ER+ breast cancer
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