Potential therapeutic targets in ARID1A-mutated cancers

Expert Opin Ther Targets. 2015;19(11):1419-22. doi: 10.1517/14728222.2015.1062879. Epub 2015 Jun 30.

Abstract

ARID1A is a subunit of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex that regulates gene expression by controlling gene accessibility. ARID1A shows one of the highest mutation rates across different human cancer types. For example, ARID1A is mutated in ∼ 50% of ovarian clear cell carcinoma (OCCC). There is considerable interest in developing cancer therapeutics that correlate with ARID1A mutational status. A recent study demonstrated a synthetic lethality by targeting EZH2 histone methyltransferase activity in ARID1A-mutated OCCC using a clinically applicable small-molecule inhibitor. The observed synthetic lethality correlated with inhibition of PI3K/AKT signaling. In addition, there is evidence indicating that ARID1A-mutated cancer may also be subjected to therapeutic intervention by targeting residual SWI/SNF activity, the PI3K/AKT pathway, the DNA damage response, the tumor immunological microenvironment and stabilizing wild-type p53. In summary, we propose EZH2 inhibitor-based combinatorial strategies for targeting ARID1A-mutated cancers.

Keywords: ARID1A; EZH2; ovarian cancer; synthetic lethality.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • DNA-Binding Proteins
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Molecular Targeted Therapy*
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Nuclear Proteins / genetics*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy
  • Transcription Factors / genetics*
  • Tumor Microenvironment

Substances

  • ARID1A protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors