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

Abstract

ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A's targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell-intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.

• Authors: Lulu Wang, Lin Yang, Chen Wang, Wei Zhao, Zhenlin Ju, Wei Zhang, Jianfeng Shen, Yang Peng, Clemens An, Yen T Luu, Shumei Song, Timothy A Yap, Jaffer A Ajani, Gordon B Mills, Xuetong Shen, Guang Peng
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 11 Pg. 5951-5966 (11 02 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 33016929 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ARID1A protein, human
• DNA-Binding Proteins
• Membrane Proteins
• Neoplasm Proteins
• STING1 protein, human
• Transcription Factors
• Checkpoint Kinase 2
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK2 protein, human
• Nucleotidyltransferases
• cGAS protein, human

Topics

• Animals
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
• Checkpoint Kinase 2 (genetics, metabolism)
• DNA-Binding Proteins (deficiency, metabolism)
• HCT116 Cells
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice
• Neoplasm Proteins (genetics, metabolism)
• Neoplasms (genetics, metabolism, pathology)
• Nucleotidyltransferases (genetics, metabolism)
• Proteolysis
• Signal Transduction
• Transcription Factors (deficiency, metabolism)