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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.

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