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

Author

Listed:
  • 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
    UTSW Simmons Cancer Center
    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
    UTSW Simmons Cancer 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
    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
    Vanderbilt University Medical Center)

  • Justin M. Balko

    (Vanderbilt University Medical Center)

  • Carlos L. Arteaga

    (Vanderbilt University Medical Center
    UTSW Simmons Cancer Center
    Vanderbilt University Medical Center)

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.

Suggested Citation

  • 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 Ericss, 2019. "Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09068-2
    DOI: 10.1038/s41467-019-09068-2
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    Cited by:

    1. Jorge Gómez Tejeda Zañudo & Romualdo Barroso-Sousa & Esha Jain & Qingchun Jin & Tianyu Li & Jorge E. Buendia-Buendia & Alyssa Pereslete & Daniel L. Abravanel & Arlindo R. Ferreira & Eileen Wrabel & Ka, 2024. "Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Wei Zhou & Wenxi Wang & Yuxin Liang & Ruibin Jiang & Fensheng Qiu & Xiying Shao & Yang Liu & Le Fang & Maowei Ni & Chenhuan Yu & Yue Zhao & Weijia Huang & Jiong Li & Michael J. Donovan & Lina Wang & J, 2023. "The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Yi Zhang & Shuyan Zhou & Yan Kai & Ya-qin Zhang & Changmin Peng & Zhuqing Li & Muhammad Jameel mughal & Belmar Julie & Xiaoyan Zheng & Junfeng Ma & Cynthia X. Ma & Min Shen & Matthew D. Hall & Shunqia, 2024. "O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. R. C. Coombes & P. D. Badman & J. P. Lozano-Kuehne & X. Liu & I. R. Macpherson & I. Zubairi & R. D. Baird & N. Rosenfeld & J. Garcia-Corbacho & N. Cresti & R. Plummer & A. Armstrong & R. Allerton & D., 2022. "Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Marta Palafox & Laia Monserrat & Meritxell Bellet & Guillermo Villacampa & Abel Gonzalez-Perez & Mafalda Oliveira & Fara Brasó-Maristany & Nusaibah Ibrahimi & Srinivasaraghavan Kannan & Leonardo Mina , 2022. "High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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