Journal Article

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

Guo, Yan, Lee, Kyung-min, Cruz, Marcelo Rocha, Nagy, Rebecca J., Balko, Justin M., Miller, Michelle, Jansen, Valerie M., Hanker, Ariella B., O’Shaughnessy, Joyce, Solovieff, Nadia, Mayer, Ingrid A., He, Wei, Guerrero-Zotano, Angel L., Arteaga, Carlos L., Schwarz, Luis J., Shyr, Yu, Bauer, Joshua A., Lanman, Richard B., Dugger, Teresa C., Formisano, Luigi, Nixon, Mellissa J., Su, Fei, Ericsson, Paula Gonzalez, Lu, Yao, Sudhan, Dhivya R., Bardia, Aditya, Sanders, Melinda E., Behdad, Amir, Servetto, Alberto, Croessmann, Sarah, Cristofanilli, Massimo

2019

Overview

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. Era+ breast cancer patients often develop resistance to endocrine therapy. Here, the authors show that FGFR1 amplification is a resistance mechanism to CDK4/6 inhibitor and endocrine therapy and that combined treatment with FGFR, CDK4/6, and anti-estrogens is a potential therapeutic strategy in Era+ breast cancer tumors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/2 / 13/51 / 13/95 / 45/70 / 45/77 / 45/90 / 45/91 / 631/67 / 631/67/1347 / Aminopyridines - administration & dosage / Aminopyridines - pharmacology / Amplification / Animals / Antagonists / Antineoplastic Agents, Hormonal - administration & dosage / Antineoplastic Agents, Hormonal - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Cancer / Circulating Tumor DNA - genetics / Clinical trials / Combined treatment / Cyclin D1 - metabolism / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - antagonists & inhibitors / Cyclin-Dependent Kinase 6 - antagonists & inhibitors / Deoxyribonucleic acid / DNA / DNA sequencing / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Endocrine therapy / Enzyme inhibitors / Female / Fibroblast growth factor receptor 1 / Fibroblast growth factor receptors / Fulvestrant / Fulvestrant - administration & dosage / Fulvestrant - pharmacology / High-Throughput Nucleotide Sequencing / Humanities and Social Sciences / Humans / Inhibitors / MCF-7 Cells / Mice / multidisciplinary / Mutation / Naphthalenes - pharmacology / Next-generation sequencing / Open reading frames / Patients / Piperazines - pharmacology / Progression-Free Survival / Proportional Hazards Models / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - pharmacology / Protein-tyrosine kinase / 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 / Science / Science (multidisciplinary) / Signal Transduction / Tyrosine / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation