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Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors

Lulu Wang1, Lin Yang1, Chen Wang2

  • 1Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The Journal of Clinical Investigation
|October 5, 2020
PubMed

Insights

Loss of ARID1A increases Chk2 levels, activating innate immunity. Inhibiting ATM/Chk2 enhances immune checkpoint blockade efficacy in ARID1A-deficient cancers, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • ARID1A is frequently mutated in cancers and is part of the SWI/SNF chromatin-remodeling complex.
  • Immune checkpoint blockade (ICB) shows promise but has limited efficacy in certain tumor types.
  • Understanding mechanisms driving ICB response in ARID1A-deficient tumors is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the role of ARID1A in regulating DNA damage response and innate immunity.
  • To identify novel therapeutic targets for combination therapy with ICB in ARID1A-deficient cancers.
  • To explore the potential of targeting the ATM/Chk2 axis to enhance anti-tumor immunity.

Main Methods:

  • Proteomic analysis of The Cancer Genome Atlas data to identify molecular alterations in ARID1A-mutated tumors.
  • Investigating the ubiquitination and degradation pathways of Chk2 in ARID1A-deficient cells.
  • Utilizing ATM/Chk2 inhibitors in preclinical models to assess impact on DNA damage, cytosolic DNA accumulation, STING activation, and anti-tumor immunity.
  • Evaluating the efficacy of ATM inhibitors combined with ICB in ARID1A-deficient and wild-type tumor models.

Main Results:

  • ARID1A deficiency leads to increased Chk2 levels by reducing its degradation via RNF8.
  • Inhibition of ATM/Chk2 axis causes replication stress and cytosolic DNA accumulation, activating STING-mediated innate immunity.
  • ARID1A and ATM/Chk2 co-mutations correlate with increased tumor-infiltrating lymphocytes and improved patient survival.
  • An ATM inhibitor selectively enhanced ICB efficacy in ARID1A-depleted tumors, but not in wild-type tumors.

Conclusions:

  • ARID1A regulates Chk2 stability, impacting innate immune responses in cancer.
  • Targeting the ATM/Chk2 axis can potentiate STING-mediated immunity in ARID1A-deficient tumors.
  • Combination therapy with ATM inhibitors and ICB represents a promising strategy for ARID1A-mutated cancers.
Keywords:
CancerCancer immunotherapyCell BiologyImmunology

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