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

Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, Sudhan DR, Guerrero-Zotano AL, Croessmann S, Guo Y, Ericsson PG, Lee KM, Nixon MJ, Schwarz LJ, Sanders ME, Dugger TC, Cruz MR, Behdad A, Cristofanilli M, Bardia A, O'Shaughnessy J, Nagy RJ, Lanman RB, Solovieff N, He W, Miller M, Su F, Shyr Y, Mayer IA, Balko JM, Arteaga CL
Nat Commun. 2019 10 (1): 1373

PMID: 30914635 · PMCID: PMC6435685 · DOI:10.1038/s41467-019-09068-2

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.

MeSH Terms (32)

Aminopyridines Animals Antineoplastic Agents, Hormonal Antineoplastic Combined Chemotherapy Protocols Breast Neoplasms Circulating Tumor DNA Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Cyclin D1 Drug Resistance, Neoplasm Female Fulvestrant High-Throughput Nucleotide Sequencing Humans MCF-7 Cells Mice Mutation Naphthalenes Piperazines Progression-Free Survival Proportional Hazards Models Protein Kinase Inhibitors Purines Pyrazoles Pyridines Quinolines Quinoxalines Receptor, Fibroblast Growth Factor, Type 1 Receptor, Fibroblast Growth Factor, Type 2 Receptors, Estrogen Signal Transduction Xenograft Model Antitumor Assays

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