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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aminopyridines / administration & dosage
-
Aminopyridines / pharmacology
-
Animals
-
Antineoplastic Agents, Hormonal / administration & dosage
-
Antineoplastic Agents, Hormonal / pharmacology
-
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
-
Breast Neoplasms / drug therapy*
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism
-
Circulating Tumor DNA / genetics*
-
Cyclin D1 / metabolism
-
Cyclin-Dependent Kinase 4 / antagonists & inhibitors
-
Cyclin-Dependent Kinase 6 / antagonists & inhibitors
-
Drug Resistance, Neoplasm / drug effects
-
Drug Resistance, Neoplasm / genetics*
-
Female
-
Fulvestrant / administration & dosage
-
Fulvestrant / pharmacology
-
High-Throughput Nucleotide Sequencing
-
Humans
-
MCF-7 Cells
-
Mice
-
Mutation
-
Naphthalenes / pharmacology
-
Piperazines / pharmacology
-
Progression-Free Survival
-
Proportional Hazards Models
-
Protein Kinase Inhibitors / administration & dosage
-
Protein Kinase Inhibitors / pharmacology
-
Purines / administration & dosage
-
Purines / pharmacology
-
Pyrazoles / pharmacology
-
Pyridines / pharmacology
-
Quinolines / pharmacology
-
Quinoxalines / pharmacology
-
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
-
Receptor, Fibroblast Growth Factor, Type 1 / genetics*
-
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
-
Receptor, Fibroblast Growth Factor, Type 2 / genetics*
-
Receptors, Estrogen / metabolism
-
Signal Transduction
-
Xenograft Model Antitumor Assays
Substances
-
Aminopyridines
-
Antineoplastic Agents, Hormonal
-
CCND1 protein, human
-
Circulating Tumor DNA
-
E-3810
-
Naphthalenes
-
Piperazines
-
Protein Kinase Inhibitors
-
Purines
-
Pyrazoles
-
Pyridines
-
Quinolines
-
Quinoxalines
-
Receptors, Estrogen
-
Cyclin D1
-
Fulvestrant
-
erdafitinib
-
FGFR1 protein, human
-
FGFR2 protein, human
-
Receptor, Fibroblast Growth Factor, Type 1
-
Receptor, Fibroblast Growth Factor, Type 2
-
Cyclin-Dependent Kinase 4
-
Cyclin-Dependent Kinase 6
-
palbociclib
-
ribociclib