LAUSR

Recent genome analyses have identified recurrent mutations in subunits of the cohesin complex in human cancer. Cohesin is a chromosomal factor that is essential for sister chromatid cohesion and cell division and that contributes to gene regulation and DNA repair. Deleterious mutations in the cohesin subunit STAG2 have been detected in about 20% of bladder cancer, 15% of Ewing sarcoma and 6% of AML/MDS patients. The mechanistic involvement of cohesin mutations in the pathogenesis of human malignancies is currently under active investigation. We hypothesized that the loss of STAG2 could alter the properties and functionalities of the cohesin complex leading to unique vulnerabilities of STAG2 mutant cells. Using CRISPR/Cas9 and RNAi in isogenic solid cancer and leukemic models we identified STAG1, a STAG2 paralog, as a strong and clean genetic vulnerability of STAG2 mutant cells. Mechanistically, STAG1 loss abrogates sister chromatid cohesion specifically in STAG2 mutant but not wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of disease relevant STAG2 mutant but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutant bladder cancer model alleviates the dependence on STAG1. Our results demonstrate that the cohesin subunits STAG1 and STAG2 act redundantly to support sister chromatid cohesion and cell viability in human cells. We have identified STAG1 as a hardwired, context independent vulnerability of STAG2 mutant cancers. Specific synthetic lethalities elicited by recurrent cohesin mutations in human tumors hold the promise for the development of selective therapeutics. Citation Format: Petra Van Der Lelij, Simone Lieb, Julian Jude, Gordana Wutz, Catarina Pereira, Katrina Falkenberg, Jozef Ban, Heinrich Kovar, Todd Waldman, Francisco Real, Mark Pearson, Norbert Kraut, Jan-Michael Peters, Johannes Zuber, Mark P. Petronczki. The cohesin subunit STAG1 is a hardwired genetic dependency of STAG2 mutant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3452. doi:10.1158/1538-7445.AM2017-3452