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

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, Sandrine Macé and James Watters ()
Additional contact information
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

Nature Communications, 2016, vol. 7, issue 1, 1-7

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12609

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