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 and Carlos L. Arteaga ()
Additional contact information
Luigi Formisano: Vanderbilt University Medical Center
Yao Lu: Vanderbilt University Medical Center
Alberto Servetto: UTSW Simmons Cancer Center
Ariella B. Hanker: Vanderbilt University Medical Center
Valerie M. Jansen: Vanderbilt University Medical Center
Joshua A. Bauer: Vanderbilt University Medical Center
Dhivya R. Sudhan: Vanderbilt University Medical Center
Angel L. Guerrero-Zotano: Vanderbilt University Medical Center
Sarah Croessmann: Vanderbilt University Medical Center
Yan Guo: Vanderbilt University School of Medicine
Paula Gonzalez Ericsson: Vanderbilt University Medical Center
Kyung-min Lee: Vanderbilt University Medical Center
Mellissa J. Nixon: Vanderbilt University Medical Center
Luis J. Schwarz: Vanderbilt University Medical Center
Melinda E. Sanders: Vanderbilt University Medical Center
Teresa C. Dugger: Vanderbilt University Medical Center
Marcelo Rocha Cruz: Robert H Lurie Comprehensive Cancer Center
Amir Behdad: Robert H Lurie Comprehensive Cancer Center
Massimo Cristofanilli: Robert H Lurie Comprehensive Cancer Center
Aditya Bardia: Harvard Medical School
Joyce O’Shaughnessy: , US Oncology
Rebecca J. Nagy: Guardant Health
Richard B. Lanman: Guardant Health
Nadia Solovieff: Novartis Institutes for Biomedical Research
Wei He: Novartis Institutes for Biomedical Research
Michelle Miller: Novartis Pharmaceuticals Corporation
Fei Su: Novartis Pharmaceuticals Corporation
Yu Shyr: Vanderbilt University School of Medicine
Ingrid A. Mayer: Vanderbilt University Medical Center
Justin M. Balko: Vanderbilt University Medical Center
Carlos L. Arteaga: Vanderbilt University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09068-2

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