Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast canceropen access
- Authors
- Formisano, Luigi; Lu, Yao; Servetto, Alberto; Hanker, Ariella B.; Jansen, Valerie M.; Bauuer, Joshua A.; Sudhan, Dhivya R.; Guerrero-Zotano, Angel L.; Croessmann, Srah; Guo, Yan; Ericsson, Paula Gonzalez; Lee, Kyung min; Nixon, Mellissa J.; Schwarz, Luis J.; Sanders, Melinda E.; Dugger, Teresa C.; Cruz, Marcelo Rocha; Behdad, Amir; Cristofanilli, Massimo; Bardia, Aditya; O'Shaughnessy, Joyce; Nagy, Rebecca J.; Lanman, Richard B.; Solovieff, Nadia; He, Wei; Miller, Michelle; Su, Fei; Shyr, Yu; Mayer, Ingrid A.; Balko, Justin M.; Arteaga, Carlos L.
- Issue Date
- Mar-2019
- Publisher
- NATURE RESEARCH
- Citation
- NATURE COMMUNICATIONS, v.10, no.1, pp.1 - 14
- Indexed
- SCIE
SCOPUS
- Journal Title
- NATURE COMMUNICATIONS
- Volume
- 10
- Number
- 1
- Start Page
- 1
- End Page
- 14
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/148135
- DOI
- 10.1038/s41467-019-09068-2
- ISSN
- 2041-1723
- 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.
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