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, James Watters

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

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Résumé

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.

langue originaleAnglais
Numéro d'article12609
journalNature Communications
Volume7
Les DOIs
étatPublié - 31 août 2016
Modification externeOui

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