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ARID1A mutant ovarian clear cell carcinoma: A clear target for synthetic lethal strategies

Joseph J Caumanns1, G Bea A Wisman1, Katrien Berns2

  • 1Department of Gynecologic Oncology, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Biochimica Et Biophysica Acta. Reviews on Cancer
|July 21, 2018
PubMed

Insights

Loss of ARID1A, common in ovarian clear cell carcinoma, creates vulnerabilities exploitable by targeting DNA repair and epigenetic factors. These synthetic lethal strategies offer new therapeutic avenues for ARID1A-mutant cancers.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Genomics

Background:

  • SWI/SNF chromatin remodeling complexes regulate gene transcription and chromatin structure.
  • Mutations in SWI/SNF subunits, particularly ARID1A, are frequent in various cancers.
  • ARID1A mutations are predominantly deleterious and linked to synthetic lethal interactions.

Purpose of the Study:

  • To review therapeutic targets synthetic lethal with ARID1A loss.
  • To focus on ARID1A-directed lethal strategies in ovarian clear cell carcinoma.
  • To highlight clinically exploitable targets for ARID1A-mutant cancers.

Main Methods:

  • Literature review of SWI/SNF complexes and ARID1A mutations.
  • Analysis of synthetic lethal interactions associated with ARID1A loss.
  • Identification of potential therapeutic targets in ARID1A-mutant cancers.

Main Results:

  • ARID1A is the most frequently mutated SWI/SNF subunit, with deleterious mutations.
  • Ovarian clear cell carcinoma exhibits the highest ARID1A mutation incidence (46-57%).
  • Several targets, including PARP, ATR, EZH2, HDAC2, HDAC6, and BRD2, show synthetic lethality with ARID1A loss.

Conclusions:

  • Targeting DNA repair proteins (PARP, ATR) and epigenetic factors (EZH2, HDACs, BRD2) represents promising synthetic lethal strategies for ARID1A-mutant cancers.
  • Exploiting ARID1A-directed vulnerabilities could lead to novel clinical treatments.
  • Further research into these targets may improve outcomes for patients with ARID1A-mutant cancers, especially ovarian clear cell carcinoma.
Keywords:
ARID1AOvarian clear cell carcinomaSWI/SNFSynthetic lethality

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