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

ABSTRACT: 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 housekeeping functions in the cell. Here we explore an approach to identify the “essential lethality” arose from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. In additional to the known synthetic-lethal interactions, this approach 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 cancers, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells leads to premature chromatid separation and dramatic extension of mitotic duration, which is accompanied by lethal failure of cell division. More importantly, depletion of SA1 renders those SA2-mutated cells not only more susceptible to DNA damage, especially double-strand breaks (DSBs), but also defective in DNA repair. Furthermore, inhibition of SA1 sensitizes the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors. This study provides a framework for the discovery of therapeutic targets in cancers that harbor specific essential gene deficiency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111004 | GEO | 2021/02/22

REPOSITORIES: GEO