Targeting the centriolar replication factor STIL synergizes with DNA damaging agents for treatment of ovarian cancer

// Noa Rabinowicz 1, 2 , Lingegowda S. Mangala 3, 4 , Kevin R. Brown 5 , Cintia Checa-Rodriguez 6 , Asher Castiel 1, 2 , Oren Moskovich 1, 2 , Giulia Zarfati 1 , Luba Trakhtenbrot 1 , Adva Levy-Barda 1 , Dahai Jiang 3, 4 , Cristian Rodriguez-Aguayo 4, 7 , Sunila Pradeep 3 , Yael van Praag 1 , Gabriel Lopez-Berestein 4, 7 , Ahuvit David 1, 2 , Ilya Novikov 9 , Pablo Huertas 6 , Robert Rottapel 10 , Anil K. Sood 3, 4, 8 , Shai Izraeli 1, 2, 11 1 Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel 2 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, Texas, USA 4 Center for RNA Interference and Non-Coding RNA, MD Anderson Cancer Center, Houston, Texas, USA 5 Donnelly Centre and The Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada 6 Department of Genetics, University of Sevilla and Centro Andaluz de Biologia Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain 7 Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas, USA 8 Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas, USA 9 Biostatistical Unit, Gertner Institute for Epidemiology and Health Policy Research, Ramat Gan, Israel 10 Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada 11 The Gene Development and Environment Pediatric Research Institute, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel Correspondence to: Shai Izraeli, email: sizraeli@sheba.health.gov.il Keywords: STIL, centrosomes, ovarian cancer, DNA damage, genomic instability Received: August 11, 2016     Accepted: February 20, 2017     Published: March 10, 2017 ABSTRACT Advanced ovarian cancer is an incurable disease. Thus, novel therapies are required. We wished to identify new therapeutic targets for ovarian cancer. ShRNA screen performed in 42 ovarian cancer cell lines identified the centriolar replication factor STIL as an essential gene for ovarian cancer cells. This was verified in-vivo in orthotopic human ovarian cancer mouse models. STIL depletion by administration of siRNA in neutral liposomes resulted in robust anti-tumor effect that was further enhanced in combination with cisplatin. Consistent with this finding, STIL depletion enhanced the extent of DNA double strand breaks caused by DNA damaging agents. This was associated with centrosomal depletion, ongoing genomic instability and enhanced formation of micronuclei. Interestingly, the ongoing DNA damage was not associated with reduced DNA repair. Indeed, we observed that depletion of STIL enhanced canonical homologous recombination repair and increased BRCA1 and RAD51 foci in response to DNA double strand breaks. Thus, inhibition of STIL significantly enhances the efficacy of DNA damaging chemotherapeutic drugs in treatment of ovarian cancer.