Unknown

Dataset Information

0

Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.


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.

SUBMITTER: Formisano L 

PROVIDER: S-EPMC6435685 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications


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-amp  ...[more]

Similar Datasets

| S-EPMC7912842 | biostudies-literature
| S-EPMC5393973 | biostudies-literature
| S-EPMC8327758 | biostudies-literature
2021-09-09 | GSE168027 | GEO
2021-09-09 | GSE168026 | GEO
2021-09-09 | GSE168024 | GEO
2021-09-09 | GSE168023 | GEO
2021-09-09 | GSE168022 | GEO
2021-09-09 | GSE181471 | GEO
| S-EPMC9932145 | biostudies-literature