Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.
Luigi FormisanoYao LuAlberto ServettoAriella B HankerValerie M JansenJoshua A BauerDhivya R SudhanAngel L Guerrero-ZotanoSarah CroessmannYan GuoPaula I Gonzalez EricssonKyung-Min LeeMellissa J NixonLuis J SchwarzMelinda E SandersTeresa C DuggerMarcelo Rocha CruzAmir BehdadMassimo CristofanilliAditya BardiaJoyce O'ShaughnessyRebecca J NagyRichard B LanmanNadia SolovieffWei HeMichelle MillerFei SuYu ShyrIngrid A MayerJustin M BalkoCarlos L ArteagaPublished in: Nature communications (2019)
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.
Keyphrases
- circulating tumor
- breast cancer cells
- newly diagnosed
- cell cycle
- end stage renal disease
- ejection fraction
- free survival
- circulating tumor cells
- tyrosine kinase
- prognostic factors
- gene expression
- dna methylation
- cell death
- clinical trial
- endothelial cells
- high throughput
- nucleic acid
- patient reported
- diabetic rats
- genome wide
- epidermal growth factor receptor