2. Academic Validation
  3. PI3K activation promotes resistance to eribulin in HER2-negative breast cancer

PI3K activation promotes resistance to eribulin in HER2-negative breast cancer

  • Br J Cancer. 2021 Apr;124(9):1581-1591. doi: 10.1038/s41416-021-01293-1.
Albert Gris-Oliver 1,  Yasir H Ibrahim 1,  Martín A Rivas 2,  Celina García-García 1,  Mònica Sánchez-Guixé 1,  Fiorella Ruiz-Pace 3,  Cristina Viaplana 3,  José M Pérez-García 4 5 6 7 8,  Antonio Llombart-Cussac 5 6,  Judit Grueso 1,  Mireia Parés 1,  Marta Guzmán 1,  Olga Rodríguez 1,  Pilar Anton 1,  Patricia Cozar 1,  Maria Teresa Calvo 1,  Alejandra Bruna 9,  Joaquín Arribas 10 11 12 13,  Carlos Caldas 14 15,  Rodrigo Dienstmann 3,  Paolo Nuciforo 13 16,  Mafalda Oliveira 4 17,  Javier Cortés  # 18 19 20 21 22,  Violeta Serra  # 23 24
Affiliations

Affiliations

  • 1 Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 2 Department of Medicine, Weil Cornell Medicine, New York, NY, USA.
  • 3 Oncology Data Science (ODysSey Group), Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 4 Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • 5 Medica Scientia Innovation Research (MedSIR), Barcelona, Spain.
  • 6 Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA.
  • 7 Breast Cancer Program, Quironsalud Group, Institute of Oncology (IOB), Barcelona, Spain.
  • 8 Breast Cancer Program, Quironsalud Group, Institute of Oncology (IOB), Madrid, Spain.
  • 9 Preclinical Modelling of Paediatric Cancer Evolution Team, Institute of Cancer Research, Sutton, UK.
  • 10 Growth Factors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 11 Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Campus de la UAB, Bellaterra, Spain.
  • 12 Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
  • 13 CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
  • 14 Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
  • 15 Cambridge Breast Unit, NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre at Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 16 Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 17 Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 18 Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. jacortes@vhio.net.
  • 19 Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. jacortes@vhio.net.
  • 20 Breast Cancer Program, Quironsalud Group, Institute of Oncology (IOB), Barcelona, Spain. jacortes@vhio.net.
  • 21 Breast Cancer Program, Quironsalud Group, Institute of Oncology (IOB), Madrid, Spain. jacortes@vhio.net.
  • 22 Breast Cancer GroupVall d'Hebron Institute of Oncology, Barcelona, Spain. jacortes@vhio.net.
  • 23 Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. vserra@vhio.net.
  • 24 CIBERONC, Instituto de Salud Carlos III, Madrid, Spain. vserra@vhio.net.
  • # Contributed equally.
PMID: 33723394 DOI: 10.1038/s41416-021-01293-1
Abstract

Background: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast Cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/Akt pathway mutations in eribulin resistance.

Methods: Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/Akt pathway.

Results: Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or Akt1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced Akt phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/Akt pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling Apoptosis, thus sensitising to eribulin treatment.

Conclusions: PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.

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