Children’s Cancer Research Institute, Vienna, Austria
Thomas Hoffmann
Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
Heinrich Kovar
Children’s Cancer Research Institute, Vienna, Austria; Department for Pediatrics, Medical University of Vienna, Vienna, Austria
Francisco X Real
Spanish National Cancer Research Centre, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain; Department de Ciències Experimentals I de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
Todd Waldman
Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington DC, United States
Mark A Pearson
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
Norbert Kraut
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
Jan-Michael Peters
Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.
