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

Nat Commun. 2016 Aug 31:7:12609. doi: 10.1038/ncomms12609.

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biopsy
  • Cell Differentiation
  • Circulating Tumor DNA / genetics
  • Circulating Tumor DNA / isolation & purification
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Liposarcoma / blood
  • Liposarcoma / drug therapy*
  • Liposarcoma / genetics
  • Liposarcoma / pathology
  • Mutation
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Response Evaluation Criteria in Solid Tumors
  • Spiro Compounds / pharmacology*
  • Spiro Compounds / therapeutic use
  • Time Factors
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Circulating Tumor DNA
  • Indoles
  • Spiro Compounds
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • SAR405838
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2