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

Authors
Formisano, LuigiLu, YaoServetto, AlbertoHanker, Ariella B.Jansen, Valerie M.Bauuer, Joshua A.Sudhan, Dhivya R.Guerrero-Zotano, Angel L.Croessmann, SrahGuo, YanEricsson, Paula GonzalezLee, Kyung minNixon, Mellissa J.Schwarz, Luis J.Sanders, Melinda E.Dugger, Teresa C.Cruz, Marcelo RochaBehdad, AmirCristofanilli, MassimoBardia, AdityaO'Shaughnessy, JoyceNagy, Rebecca J.Lanman, Richard B.Solovieff, NadiaHe, WeiMiller, MichelleSu, FeiShyr, YuMayer, 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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