CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary

Authors: Yibo Xue, Brian Meehan, Elizabeth Macdonald, Sriram Venneti, Xue Qing D. Wang, Leora Witkowski, Petar Jelinic, Tim Kong, Daniel Martinez, Geneviève Morin, Michelle Firlit, Atefeh Abedini, Radia M. Johnson, Regina Cencic, Jay Patibandla, Hongbo Chen, Andreas I. Papadakis, Aurelie Auguste, Iris de Rink, Ron M. Kerkhoven, Nicholas Bertos, Walter H. Gotlieb, Blaise A. Clarke, Alexandra Leary, Michael Witcher, Marie-Christine Guiot, Jerry Pelletier, Josée Dostie, Morag Park, Alexander R. Judkins, Ralf Hass, Douglas A. Levine, Janusz Rak, Barbara Vanderhyden, William D. Foulkes, Sidong Huang


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/p16INK4a-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.

Source: Nature Communications, 2019; 10 (1)