Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

Mol Cancer Ther. 2016 Jul;15(7):1472-84. doi: 10.1158/1535-7163.MCT-15-0554. Epub 2016 Jun 30.

Abstract

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1-S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / drug therapy
  • Adenocarcinoma, Clear Cell / genetics*
  • Adenocarcinoma, Clear Cell / pathology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Dasatinib / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Expression Profiling
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Synthetic Lethal Mutations*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • ARID1A protein, human
  • Antineoplastic Agents
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Retinoblastoma Protein
  • Transcription Factors
  • Proto-Oncogene Proteins p21(ras)
  • Dasatinib