Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer
- Title
- Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer
- Author
- 이경민
- Keywords
- ACQUIRED-RESISTANCE; PHARMACOLOGICAL INHIBITION; AMPLIFICATION; EXPRESSION; THERAPY; GROWTH; COMBINATION; PALBOCICLIB; MUTATIONS; ABEMACICLIB
- Issue Date
- 2019-03
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- NATURE COMMUNICATIONS, v. 10, article no. 1373
- 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.
- URI
- https://www.nature.com/articles/s41467-019-09068-2https://repository.hanyang.ac.kr/handle/20.500.11754/160679
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-019-09068-2
- Appears in Collections:
- COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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