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Cellular and Molecular Biology

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

British Journal of Cancer volume 124, pages 1581–1591 (2021)Cite this article

Subjects

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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Fig. 1: PIK3CA-activating mutations correlate with resistance to eribulin in vitro.
Fig. 2: PIK3CA/AKT1-activating mutations do not predict primary resistance to eribulin in vivo.
Fig. 3: PI3K inhibition increases the activity of eribulin in vitro and in vivo.
Fig. 4: PI3K inhibition reverses secondary resistance to eribulin single agent and restores therapy response.
Fig. 5: Downmodulation of p21 re-sensitises to eribulin treatment.

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Acknowledgements

We are grateful to all the patients who kindly consented to the use of their tumours to develop this study and to all the personnel involved in sample collection from the Breast Surgical Unit, Breast Cancer Centre, and Department of Radiology Vall d’Hebron University Hospital and Molecular Oncology Group at Vall d’Hebron Institute of Oncology (VHIO). We also thank the Cellex Foundation for providing research facilities and equipment, as well as Ana Vivancos and the Cancer Genomics Group at VHIO and Joanne Soong and the Centre for Molecular Oncology at the MSKCC for providing technical and analytical support with the patient and PDX sequencing.

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Author notes

  1. These authors contributed equally: Javier Cortés, Violeta Serra

Authors and Affiliations

  1. Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Albert Gris-Oliver, Yasir H. Ibrahim, Celina García-García, Mònica Sánchez-Guixé, Judit Grueso, Mireia Parés, Marta Guzmán, Olga Rodríguez, Pilar Anton, Patricia Cozar, Maria Teresa Calvo & Violeta Serra

  2. Department of Medicine, Weil Cornell Medicine, New York, NY, USA

    Martín A. Rivas

  3. Oncology Data Science (ODysSey Group), Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Fiorella Ruiz-Pace, Cristina Viaplana & Rodrigo Dienstmann

  4. Department of Medical Oncology, Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    José M. Pérez-García & Mafalda Oliveira

  5. Medica Scientia Innovation Research (MedSIR), Barcelona, Spain

    José M. Pérez-García, Antonio Llombart-Cussac & Javier Cortés

  6. Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA

    José M. Pérez-García, Antonio Llombart-Cussac & Javier Cortés

  7. Breast Cancer Program, Quironsalud Group, Institute of Oncology (IOB), Barcelona, Spain

    José M. Pérez-García & Javier Cortés

  8. Breast Cancer Program, Quironsalud Group, Institute of Oncology (IOB), Madrid, Spain

    José M. Pérez-García & Javier Cortés

  9. Preclinical Modelling of Paediatric Cancer Evolution Team, Institute of Cancer Research, Sutton, UK

    Alejandra Bruna

  10. Growth Factors Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Joaquín Arribas

  11. Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Campus de la UAB, Bellaterra, Spain

    Joaquín Arribas

  12. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

    Joaquín Arribas

  13. CIBERONC, Instituto de Salud Carlos III, Madrid, Spain

    Joaquín Arribas, Paolo Nuciforo & Violeta Serra

  14. Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK

    Carlos Caldas

  15. Cambridge Breast Unit, NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre at Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Carlos Caldas

  16. Molecular Oncology Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Paolo Nuciforo

  17. Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Mafalda Oliveira

  18. Breast Cancer GroupVall d’Hebron Institute of Oncology, Barcelona, Spain

    Javier Cortés

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  1. Albert Gris-Oliver
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Contributions

A.G.-O., J.C. and V.S. designed the experiments and wrote the manuscript. A.G.-O., Y.H.I, M.A.R., C.G.-G., M.S.-G., F.R.-P., C.V., J.M.P.-G., A.L.-C., J.G., M.P., M.G., O.R., P.A., P.C., M.T.C., A.B., J.A., C.C., R.D., P.N., M.O., J.C. and V.S. helped in the acquisition of data and/or provided technical support (provided animals, acquired and managed patients, provided facilities, etc.). A.G.-O., Y.H.I., M.A.R., C.G.-G., M.S.-G., F.R.-P., C.V., R.D., M.O., J.C. and V.S. contributed in the analysis of data (e.g. statistical analysis, biostatistics, computational analysis and construction of databases).

Corresponding authors

Correspondence to Javier Cortés or Violeta Serra.

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Fresh tumour samples from patients with breast cancer were collected following an Institutional Research Board-approved protocol and the associated written informed consent. The study was compliant with the Declaration of Helsinki.

Experiments were conducted following the European Union’s animal care directive (2010/63/EU) and were approved by the Ethical Committee of Animal Experimentation of the Vall d’Hebron Research Institute, the Catalan Government or by the National Research Ethics Service, Cambridgeshire (ref. 35 and https://caldaslab.cruk.cam.ac.uk/bcape/).

Data availability

All data generated or analysed during this study are included in this published article [and its Supplementary information files].

Competing interests

V.S. declares non-commercial research agreements with Genentech and Novartis. J.C. reports consulting for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology and Boehringer Ingelheim; honoraria for Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme and Daiichi Sankyo; research funding to the Institution: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardanth Health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C and Queen Mary University of London; stock, patents and intellectual property of MedSIR; and travel, accommodation and other expenses for Roche, Novartis, Eisai, Pfizer and Daiichi Sankyo. M.O. declares research support from AstraZeneca, Genentech and Philips Healthcare; consultant role for Roche, GSK, PUMA Biotechnology and AstraZeneca; and has received honoraria from Roche. M.S.-G. is on the scientific advisory board of Menarini Ricerche and the Bioscience Institute, has received research funds from Puma Biotechnology, Daiichi-Sankio, Targimmune, Immunomedics and Menarini Ricerche, and is a cofounder of Medendi.org. C.C. is a member of AstraZeneca’s External Science Panel, of Illumina’s Scientific Advisory Board and is a recipient of research grants (administered by the University of Cambridge) from AstraZeneca, Genentech, Roche and Servier. R.D. is on advisory role of AstraZeneca, Roche and Boehringer-Ingelheim and has received speaker’s fees from Roche, Symphogen, IPSEN, Amgen, Servier, Sanofi and MSD; and research support from Merck. J.M.P.-G. reports an advisory role with Roche and Lilly. A.L.-C. has been a consultant for Roche, GlaxoSmithKline, Novartis, Celgene, Eisai and AstraZeneca in the previous 12 months and has stock options for Medica Scientia Innovation Research SL (MedSIR). All other authors declare no competing interests.

Funding information

We acknowledge the GHD-Pink programme, the FERO Foundation and the Orozco Family for supporting this study [to V.S.], as well as Fundación Mútua Madrileña [to J.C.]. This study has also been supported by the Catalan Agency AGAUR [2017 SGR 540 to V.S.]. V.S. is supported by the Miguel Servet Programme (ISCIII) [CPII19/00033]. A.G.-O. was awarded with a fellowship from the Agència de Gestió d’Ajuts Universitaris i de Recerca (FI-AGAUR, 2015 FI_B 01075), and M.S.-G. with a Marie Slodowska-Curie Innovative Training Networks (MSCA-ITN) Ph.D. fellowship (H2020-MSCA-ITN-2015_675392). The xenograft programme in the Caldas Laboratory was supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN).

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Gris-Oliver, A., Ibrahim, Y.H., Rivas, M.A. et al. PI3K activation promotes resistance to eribulin in HER2-negative breast cancer. Br J Cancer 124, 1581–1591 (2021). https://doi.org/10.1038/s41416-021-01293-1

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