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

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



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 made available2019
Geographical coverageUSA

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