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High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Author

Listed:
  • Marta Palafox

    (Vall d’Hebron Institute of Oncology)

  • Laia Monserrat

    (Vall d’Hebron Institute of Oncology)

  • Meritxell Bellet

    (Vall d’Hebron Institute of Oncology
    Hospital Vall d’Hebron)

  • Guillermo Villacampa

    (Vall d’Hebron Institute of Oncology)

  • Abel Gonzalez-Perez

    (Institute for Research in Biomedicine (IRB Barcelona)
    Universitat Pompeu Fabra)

  • Mafalda Oliveira

    (Vall d’Hebron Institute of Oncology
    Hospital Vall d’Hebron)

  • Fara Brasó-Maristany

    (August Pi i Sunyer Biomedical Research Institute (IDIBAPS))

  • Nusaibah Ibrahimi

    (Service de Biostatistique et d’Epidémiologie, Gustave Roussy
    University Paris-Saclay)

  • Srinivasaraghavan Kannan

    (Bioinformatics Institute (A*STAR))

  • Leonardo Mina

    (Medica Scientia Innovation Research (MedSIR))

  • Maria Teresa Herrera-Abreu

    (The Breast Cancer Now Research Centre)

  • Andreu Òdena

    (Vall d’Hebron Institute of Oncology)

  • Mònica Sánchez-Guixé

    (Vall d’Hebron Institute of Oncology)

  • Marta Capelán

    (Vall d’Hebron Institute of Oncology
    Hospital Vall d’Hebron)

  • Analía Azaro

    (Vall d’Hebron Institute of Oncology
    Hospital Vall d’Hebron)

  • Alejandra Bruna

    (The Institute of Cancer Research)

  • Olga Rodríguez

    (Vall d’Hebron Institute of Oncology)

  • Marta Guzmán

    (Vall d’Hebron Institute of Oncology)

  • Judit Grueso

    (Vall d’Hebron Institute of Oncology)

  • Cristina Viaplana

    (Vall d’Hebron Institute of Oncology)

  • Javier Hernández

    (Vall d’Hebron Institute of Research (VHIR))

  • Faye Su

    (Novartis Pharmaceuticals)

  • Kui Lin

    (Genentech, Inc., South San Francisco)

  • Robert B. Clarke

    (Breast Biology Group, Manchester Breast Centre)

  • Carlos Caldas

    (Cancer Research UK)

  • Joaquín Arribas

    (CIBERONC, Vall d’Hebron Institute of Oncology
    Vall d’Hebron Institute of Oncology
    Universitat Autònoma de Barcelona
    IMIM (Hospital del Mar Medical Research Institute))

  • Stefan Michiels

    (Service de Biostatistique et d’Epidémiologie, Gustave Roussy
    University Paris-Saclay)

  • Alicia García-Sanz

    (Medica Scientia Innovation Research (MedSIR))

  • Nicholas C. Turner

    (The Breast Cancer Now Research Centre)

  • Aleix Prat

    (August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
    University of Barcelona
    Hospital Clinic
    SOLTI Breast Cancer Research Group)

  • Paolo Nuciforo

    (Vall d’Hebron Institute of Oncology)

  • Rodrigo Dienstmann

    (Vall d’Hebron Institute of Oncology)

  • Chandra S. Verma

    (Bioinformatics Institute (A*STAR)
    Nanyang Technological University
    National University of Singapore)

  • Nuria Lopez-Bigas

    (Institute for Research in Biomedicine (IRB Barcelona)
    Universitat Pompeu Fabra
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Maurizio Scaltriti

    (Memorial Sloan-Kettering Cancer Center)

  • Monica Arnedos

    (Gustave Roussy
    Inserm Unit U981)

  • Cristina Saura

    (Vall d’Hebron Institute of Oncology
    Hospital Vall d’Hebron)

  • Violeta Serra

    (Vall d’Hebron Institute of Oncology
    CIBERONC, Vall d’Hebron Institute of Oncology)

Abstract

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32828-6
    DOI: 10.1038/s41467-022-32828-6
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    References listed on IDEAS

    as
    1. Peter Priestley & Jonathan Baber & Martijn P. Lolkema & Neeltje Steeghs & Ewart Bruijn & Charles Shale & Korneel Duyvesteyn & Susan Haidari & Arne Hoeck & Wendy Onstenk & Paul Roepman & Mircea Voda & , 2019. "Pan-cancer whole-genome analyses of metastatic solid tumours," Nature, Nature, vol. 575(7781), pages 210-216, November.
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    3. Yingdai Gao & Peng Yang & Hongmei Shen & Hui Yu & Xianmin Song & Liyan Zhang & Peng Zhang & Haizi Cheng & Zhaojun Xie & Sha Hao & Fang Dong & Shihui Ma & Qing Ji & Patrick Bartlow & Yahui Ding & Liron, 2015. "Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
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