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

Luigi Formisano; Yao Lu; Alberto Servetto; Ariella B. Hanker; Valerie M. Jansen; Joshua A. Bauer; Dhivya R. Sudhan; Angel L. Guerrero-Zotano; Sarah Croessmann; Yan Guo; Paula Gonzalez Ericsson; Kyung min Lee; Mellissa J. Nixon; Luis J. Schwarz; Melinda E. Sanders; Teresa C. Dugger; Marcelo Rocha Cruz; Amir Behdad; Massimo Cristofanilli; Aditya Bardia; Joyce O’Shaughnessy; Rebecca J. Nagy; Richard B. Lanman; Nadia Solovieff; Wei He; Michelle Miller; Fei Su; Yu Shyr; Ingrid A. Mayer; Justin M. Balko; Carlos L. Arteaga

doi:10.1038/s41467-019-09068-2

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

Luigi Formisano, Yao Lu, Alberto Servetto, Ariella B. Hanker, Valerie M. Jansen, Joshua A. Bauer, Dhivya R. Sudhan, Angel L. Guerrero-Zotano, Sarah Croessmann, Yan Guo, Paula Gonzalez Ericsson, Kyung min Lee, Mellissa J. Nixon, Luis J. Schwarz, Melinda E. Sanders, Teresa C. Dugger, Marcelo Rocha Cruz, Amir Behdad, Massimo Cristofanilli, Aditya BardiaJoyce O’Shaughnessy, Rebecca J. Nagy, Richard B. Lanman, Nadia Solovieff, Wei He, Michelle Miller, Fei Su, Yu Shyr, Ingrid A. Mayer, Justin M. Balko, Carlos L. Arteaga

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229 Scopus citations

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.

Original language	English (US)
Article number	1373
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09068-2
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-019-09068-2

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Formisano, L., Lu, Y., Servetto, A., Hanker, A. B., Jansen, V. M., Bauer, J. A., Sudhan, D. R., Guerrero-Zotano, A. L., Croessmann, S., Guo, Y., Ericsson, P. G., Lee, K. M., Nixon, M. J., Schwarz, L. J., Sanders, M. E., Dugger, T. C., Cruz, M. R., Behdad, A., Cristofanilli, M., ... Arteaga, C. L. (2019). Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nature communications, 10(1), Article 1373. https://doi.org/10.1038/s41467-019-09068-2

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 2019, 'Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer', Nature communications, vol. 10, no. 1, 1373. https://doi.org/10.1038/s41467-019-09068-2

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title = "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.",

author = "Luigi Formisano and Yao Lu and Alberto Servetto and Hanker, {Ariella B.} and Jansen, {Valerie M.} and Bauer, {Joshua A.} and Sudhan, {Dhivya R.} and Guerrero-Zotano, {Angel L.} and Sarah Croessmann and Yan Guo and Ericsson, {Paula Gonzalez} and Lee, {Kyung min} and Nixon, {Mellissa J.} and Schwarz, {Luis J.} and Sanders, {Melinda E.} and Dugger, {Teresa C.} and Cruz, {Marcelo Rocha} and Amir Behdad and Massimo Cristofanilli and Aditya Bardia and Joyce O{\textquoteright}Shaughnessy and Nagy, {Rebecca J.} and Lanman, {Richard B.} and Nadia Solovieff and Wei He and Michelle Miller and Fei Su and Yu Shyr and Mayer, {Ingrid A.} and Balko, {Justin M.} and Arteaga, {Carlos L.}",

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AU - Formisano, Luigi

AU - Lu, Yao

AU - Servetto, Alberto

AU - Hanker, Ariella B.

AU - Jansen, Valerie M.

AU - Bauer, Joshua A.

AU - Sudhan, Dhivya R.

AU - Guerrero-Zotano, Angel L.

AU - Croessmann, Sarah

AU - Guo, Yan

AU - Ericsson, Paula Gonzalez

AU - Lee, Kyung min

AU - Nixon, Mellissa J.

AU - Schwarz, Luis J.

AU - Sanders, Melinda E.

AU - Dugger, Teresa C.

AU - Cruz, Marcelo Rocha

AU - Behdad, Amir

AU - Cristofanilli, Massimo

AU - Bardia, Aditya

AU - O’Shaughnessy, Joyce

AU - Nagy, Rebecca J.

AU - Lanman, Richard B.

AU - Solovieff, Nadia

AU - He, Wei

AU - Miller, Michelle

AU - Su, Fei

AU - Shyr, Yu

AU - Mayer, Ingrid A.

AU - Balko, Justin M.

AU - Arteaga, Carlos L.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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

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