Scientific Publications Database

Article Title: CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary
Authors: Xue, Yibo; Meehan, Brian; Macdonald, Elizabeth; Venneti, Sriram; Wang, Xue Qing D.; Witkowski, Leora; Jelinic, Petar; Kong, Tim; Martinez, Daniel; Morin, Genevieve; Firlit, Michelle; Abedini, Atefeh; Johnson, Radia M.; Cencic, Regina; Patibandla, Jay; Chen, Hongbo; Papadakis, Andreas I.; Auguste, Aurelie; de Rink, Iris; Kerkhoven, Ron M.; Bertos, Nicholas; Gotlieb, Walter H.; Clarke, Blaise A.; Leary, Alexandra; Witcher, Michael; Guiot, Marie-Christine; Pelletier, Jerry; Dostie, Josee; Park, Morag; Judkins, Alexander R.; Hass, Ralf; Levine, Douglas A.; Rak, Janusz; Vanderhyden, Barbara; Foulkes, William D.; Huang, Sidong
Journal: NATURE COMMUNICATIONS Volume 10
Date of Publication:2019
Abstract:
Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16(INK4a)-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.