Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

• Published in: The Journal of clinical investigation Vol. 128; no. 7; pp. 2951 - 2965
• Main Authors: Liu, Yunhua, Xu, Hanchen, Van der Jeught, Kevin, Li, Yujing, Liu, Sheng, Zhang, Lu, Fang, Yuanzhang, Zhang, Xinna, Radovich, Milan, Schneider, Bryan P, He, Xiaoming, Huang, Cheng, Zhang, Chi, Wan, Jun, Ji, Guang, Lu, Xiongbin
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2018
• Subjects: Adenosine diphosphate; Animals; Antigens, Nuclear - chemistry; Antigens, Nuclear - genetics; Bioinformatics; Biomedical research; Bladder cancer; BRCA1 protein; Cancer; Cancer therapies; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell division; Cell growth; Cell Line, Tumor; Cell proliferation; Cell survival; Chromosomal Proteins, Non-Histone - antagonists & inhibitors; Chromosomal Proteins, Non-Histone - chemistry; Chromosomal Proteins, Non-Histone - genetics; Chromosomes; Cohesin; Cohesins; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA repair; Dosage and administration; Drug therapy; Ewing's sarcoma; Female; Gene expression; Gene Knockdown Techniques; Gene mutation; Genes, Essential; Genetic aspects; Genomes; Genomics; Humans; Lethality; Mice; Mice, Nude; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Phthalazines - pharmacology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Protein Subunits - antagonists & inhibitors; Protein Subunits - chemistry; Protein Subunits - genetics; Ribose; RNA polymerase; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - genetics; Therapeutic applications; Therapeutics; Tumors; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Xenograft Model Antitumor Assays; Oncology; Therapeutics; Cancer
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI98727

A synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.