Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis)

• Published in: Cell death & disease 2024-05, Vol.15 (5), p.375-12, Article 375
• Main Authors: Wang, Zihuan, Zhang, Xu, Luo, Yuchen, Song, Yijiang, Xiang, Cheng, He, Yilin, Wang, Kejin, Yu, Yingnan, Wang, Zhen, Peng, Wenxuan, Ding, Yi, Liu, Side, Wu, Changjie
• Format: Article
• Language: English
• Subjects: 13/2; 13/31; 14/34; 38/89; 42/109; 64/60; 692/699/67/1059/602; 82/80; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Culture; Cell Line, Tumor; Chromatin remodeling; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Furans; HCT116 Cells; Humans; Immunology; Lethality; Life Sciences; MDM2 protein; Mice; Mice, Nude; p53 Protein; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Therapeutic targets; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06751-1

ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is frequently mutated in various cancer types and has emerged as a potential therapeutic target. In this study, we observed that ARID1A-deficient colorectal cancer (CRC) cells showed synthetic lethal effects with a p53 activator, RITA (reactivating p53 and inducing tumor apoptosis). RITA, an inhibitor of the p53-MDM2 interaction, exhibits increased sensitivity in ARID1A-deficient cells compared to ARID1A wild-type cells. Mechanistically, the observed synthetic lethality is dependent on both p53 activation and DNA damage accumulation, which are regulated by the interplay between ARID1A and RITA. ARID1A loss exhibits an opposing effect on p53 targets, leading to decreased p21 expression and increased levels of proapoptotic genes, PUMA and NOXA, which is further potentiated by RITA treatment, ultimately inducing cell apoptosis. Meanwhile, ARID1A loss aggravates RITA-induced DNA damage accumulation by downregulating Chk2 phosphorylation. Taken together, ARID1A loss significantly heightens sensitivity to RITA in CRC, revealing a novel synthetic lethal interaction between ARID1A and RITA. These findings present a promising therapeutic approach for colorectal cancer characterized by ARID1A loss-of-function mutations.