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.

Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer / 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.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - (2019), pp. 1-14. [10.1038/s41467-019-09068-2]

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

Formisano L;Servetto A;
2019

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.
2019
Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer / 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.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - (2019), pp. 1-14. [10.1038/s41467-019-09068-2]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/751743
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