lucitanib and erdafitinib

Developments in breast cancer biology over the last years have permitted deconstructing the molecular profile of the most relevant breast cancer subtypes. This has led to an increase in therapeutic options, including more effective personalized therapy for breast cancer and substantial improvements in patient outcomes. Although currently there are only a few targeted therapies approved for metastatic breast cancer, the discovery of druggable kinase gene alterations has radically changed cancer treatment by providing novel and successfully actionable drug targets. Fibroblast growth factors and their receptors (FGFRs) participate in different physiologic processes and also play an essential role in cancer cell proliferation, survival, differentiation, migration, and apoptosis. This article summarizes the main molecular alterations of FGFRs, as well as the available preclinical and clinical data with FGFR inhibitors in breast cancer, and discusses new opportunities for the clinical development of these agents in patients with breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Female; Fibroblast Growth Factors; Humans; Naphthalenes; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quinolines; Quinolones; Quinoxalines; Receptors, Fibroblast Growth Factor; Signal Transduction

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.

Topics: Aminopyridines; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Circulating Tumor DNA; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; 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