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Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor

Author

Listed:
  • Dejan Juric

    (Massachusetts General Hospital Cancer Center, 55 Fruit Street)

  • Pau Castel

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Malachi Griffith

    (Washington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USA
    Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
    The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA)

  • Obi L. Griffith

    (Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
    The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA
    Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA)

  • Helen H. Won

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA
    Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Haley Ellis

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Saya H. Ebbesen

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Benjamin J. Ainscough

    (The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA)

  • Avinash Ramu

    (The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA)

  • Gopa Iyer

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA
    Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Ronak H. Shah

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Tiffany Huynh

    (Massachusetts General Hospital Cancer Center, 55 Fruit Street)

  • Mari Mino-Kenudson

    (Massachusetts General Hospital Cancer Center, 55 Fruit Street)

  • Dennis Sgroi

    (Massachusetts General Hospital Cancer Center, 55 Fruit Street)

  • Steven Isakoff

    (Massachusetts General Hospital Cancer Center, 55 Fruit Street)

  • Ashraf Thabet

    (Massachusetts General Hospital Cancer Center, 55 Fruit Street)

  • Leila Elamine

    (Massachusetts General Hospital Cancer Center, 55 Fruit Street)

  • David B. Solit

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA
    Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Scott W. Lowe

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA
    Howard Hughes Medical Institute, Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Cornelia Quadt

    (Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland)

  • Malte Peters

    (Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland)

  • Adnan Derti

    (Oncology Translational Medicine, Novartis Institutes for BioMedical Research)

  • Robert Schegel

    (Oncology Translational Medicine, Novartis Institutes for BioMedical Research)

  • Alan Huang

    (Oncology Translational Medicine, Novartis Institutes for BioMedical Research)

  • Elaine R. Mardis

    (Washington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USA
    Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
    The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA
    Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA)

  • Michael F. Berger

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA
    Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • José Baselga

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA
    Breast Medicine Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

  • Maurizio Scaltriti

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA)

Abstract

A study of genome evolution in a metastatic breast cancer bearing an activating PIK3CA mutation, following treatment with the PI(3)Kα inhibitor BYL719, shows that all metastatic lesions, when compared to the pre-treatment tumour, had lost a copy of PTEN; parallel genetic evolution of separate sites with different PTEN genomic alterations had led to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.

Suggested Citation

  • Dejan Juric & Pau Castel & Malachi Griffith & Obi L. Griffith & Helen H. Won & Haley Ellis & Saya H. Ebbesen & Benjamin J. Ainscough & Avinash Ramu & Gopa Iyer & Ronak H. Shah & Tiffany Huynh & Mari M, 2015. "Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor," Nature, Nature, vol. 518(7538), pages 240-244, February.
    • Handle: RePEc:nat:nature:v:518:y:2015:i:7538:d:10.1038_nature13948
    DOI: 10.1038/nature13948
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    Cited by:

    1. Ilya G. Serebriiskii & Valery Pavlov & Rossella Tricarico & Grigorii Andrianov & Emmanuelle Nicolas & Mitchell I. Parker & Justin Newberg & Garrett Frampton & Joshua E. Meyer & Erica A. Golemis, 2022. "Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. 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.

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