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TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma

Author

Listed:
  • Joonil Jung

    (Sanofi Oncology)

  • Joon Sang Lee

    (Sanofi Oncology)

  • Mark A. Dickson

    (Memorial Sloan Kettering Cancer Center)

  • Gary K. Schwartz

    (Columbia University Medical Center)

  • Axel Le Cesne

    (Gustave Roussy)

  • Andrea Varga

    (Gustave Roussy)

  • Rastilav Bahleda

    (Gustave Roussy)

  • Andrew J. Wagner

    (Center for Sarcoma and Bone Oncology, Dana–Farber Cancer Institute)

  • Edwin Choy

    (Massachusetts General Hospital)

  • Maja J. de Jonge

    (Erasmus MC Cancer Institute)

  • Madelyn Light

    (Sanofi Oncology)

  • Steve Rowley

    (Sanofi Oncology)

  • Sandrine Macé

    (Sanofi Oncology)

  • James Watters

    (Sanofi Oncology)

Abstract

In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2–p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules.

Suggested Citation

  • Joonil Jung & Joon Sang Lee & Mark A. Dickson & Gary K. Schwartz & Axel Le Cesne & Andrea Varga & Rastilav Bahleda & Andrew J. Wagner & Edwin Choy & Maja J. de Jonge & Madelyn Light & Steve Rowley & S, 2016. "TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma," Nature Communications, Nature, vol. 7(1), pages 1-7, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12609
    DOI: 10.1038/ncomms12609
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    Cited by:

    1. Mrinal M. Gounder & Narasimhan P. Agaram & Sally E. Trabucco & Victoria Robinson & Richard A. Ferraro & Sherri Z. Millis & Anita Krishnan & Jessica Lee & Steven Attia & Wassim Abida & Alexander Drilon, 2022. "Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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