Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer
| Autor: | Valerie M. Jansen, Yao Lu, Paula Gonzalez Ericsson, Wei He, Luis J. Schwarz, Richard B. Lanman, Dhivya R. Sudhan, Yu Shyr, Teresa C. Dugger, Yan Guo, Carlos L. Arteaga, Marcelo Rocha Cruz, Alberto Servetto, Ingrid A. Mayer, Amir Behdad, Aditya Bardia, Luigi Formisano, Sarah Croessmann, Nadia Solovieff, Angel Guerrero-Zotano, Fei Su, Michelle Miller, Justin M. Balko, Mellissa J. Nixon, Joyce O'Shaughnessy, Ariella B. Hanker, Kyungmin Lee, Melinda E. Sanders, Massimo Cristofanilli, Joshua A. Bauer, Rebecca J. Nagy |
|---|---|
| Přispěvatelé: | 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. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pyridines General Physics and Astronomy Aminopyridines 02 engineering and technology Drug resistance Tyrosine-kinase inhibitor Piperazines Circulating Tumor DNA chemistry.chemical_compound Mice Erdafitinib Antineoplastic Combined Chemotherapy Protocols Cyclin D1 lcsh:Science Abemaciclib Fulvestrant cancer cell Multidisciplinary drug High-Throughput Nucleotide Sequencing 021001 nanoscience & nanotechnology Progression-Free Survival 3. Good health inhibitor Receptors Estrogen MCF-7 Cells Quinolines Female biological phenomena cell phenomena and immunity 0210 nano-technology medicine.drug Signal Transduction identification method Antineoplastic Agents Hormonal medicine.drug_class Science Breast Neoplasms Palbociclib Naphthalenes General Biochemistry Genetics and Molecular Biology Article resistance 03 medical and health sciences Breast cancer Quinoxalines medicine Animals Humans Progression-free survival Receptor Fibroblast Growth Factor Type 1 Receptor Fibroblast Growth Factor Type 2 Protein Kinase Inhibitors Proportional Hazards Models business.industry Cyclin-Dependent Kinase 4 General Chemistry DNA Cyclin-Dependent Kinase 6 medicine.disease Xenograft Model Antitumor Assays stomatognathic diseases 030104 developmental biology chemistry Drug Resistance Neoplasm Purines Mutation Cancer research Pyrazoles lcsh:Q survival tumor business |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|