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 & 11 others 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article number1373
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

Fingerprint

breast
inhibitors
cancer
Breast Neoplasms
Protein-Tyrosine Kinases
Amplification
progressions
Tumors
tyrosine
MCF-7 Cells
DNA
Heterografts
tumors
deoxyribonucleic acid
Cells
sequencing
mutations
cells
Drug Resistance
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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. / Formisano, Luigi; Lu, Yao; Servetto, Alberto; Hanker, Ariella B.; Jansen, Valerie M.; Bauer, Joshua A.; Sudhan, Dhivya R.; Guerrero-Zotano, Angel L.; Croessmann, Sarah; Guo, Yan; Ericsson, Paula Gonzalez; Lee, Kyung min; Nixon, Mellissa J.; Schwarz, Luis J.; Sanders, Melinda E.; Dugger, Teresa C.; Cruz, Marcelo Rocha; Behdad, Amir; Cristofanilli, Massimo; Bardia, Aditya; O’Shaughnessy, Joyce; Nagy, Rebecca J.; Lanman, Richard B.; Solovieff, Nadia; He, Wei; Miller, Michelle; Su, Fei; Shyr, Yu; Mayer, Ingrid A.; Balko, Justin M.; Arteaga, Carlos L.

In: Nature communications, Vol. 10, No. 1, 1373, 01.12.2019.

Research output: Contribution to journalArticle

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
Formisano, Luigi ; Lu, Yao ; Servetto, Alberto ; Hanker, Ariella B. ; Jansen, Valerie M. ; Bauer, Joshua A. ; Sudhan, Dhivya R. ; Guerrero-Zotano, Angel L. ; Croessmann, Sarah ; Guo, Yan ; Ericsson, Paula Gonzalez ; Lee, Kyung min ; Nixon, Mellissa J. ; Schwarz, Luis J. ; Sanders, Melinda E. ; Dugger, Teresa C. ; Cruz, Marcelo Rocha ; Behdad, Amir ; Cristofanilli, Massimo ; Bardia, Aditya ; O’Shaughnessy, Joyce ; Nagy, Rebecca J. ; Lanman, Richard B. ; Solovieff, Nadia ; He, Wei ; Miller, Michelle ; Su, Fei ; Shyr, Yu ; Mayer, Ingrid A. ; Balko, Justin M. ; Arteaga, Carlos L. / Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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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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.

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