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

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 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 () and Sidong Huang ()
Additional contact information
Yibo Xue: McGill University
Brian Meehan: McGill University
Elizabeth Macdonald: Ottawa Hospital Research Institute
Sriram Venneti: University of Michigan Medical School
Xue Qing D. Wang: McGill University
Leora Witkowski: McGill University
Petar Jelinic: NYU Langone Medical Center
Tim Kong: McGill University
Daniel Martinez: Children’s Hospital of Philadelphia Research Institute
Geneviève Morin: McGill University
Michelle Firlit: NYU Langone Medical Center
Atefeh Abedini: Ottawa Hospital Research Institute
Radia M. Johnson: McGill University
Regina Cencic: McGill University
Jay Patibandla: NYU Langone Medical Center
Hongbo Chen: Sun Yat-Sat University
Andreas I. Papadakis: McGill University
Aurelie Auguste: Gustave Roussy, INSERM U981
Iris Rink: The Netherlands Cancer Institute
Ron M. Kerkhoven: The Netherlands Cancer Institute
Nicholas Bertos: McGill University
Walter H. Gotlieb: McGill University
Blaise A. Clarke: University of Toronto, University Health Network
Alexandra Leary: Gustave Roussy, INSERM U981
Michael Witcher: McGill University
Marie-Christine Guiot: McGill University Health Centre
Jerry Pelletier: McGill University
Josée Dostie: McGill University
Morag Park: McGill University
Alexander R. Judkins: Keck School of Medicine of University of Southern California
Ralf Hass: Medical University Hannover
Douglas A. Levine: NYU Langone Medical Center
Janusz Rak: McGill University
Barbara Vanderhyden: Ottawa Hospital Research Institute
William D. Foulkes: McGill University
Sidong Huang: McGill University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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/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.

Date: 2019
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DOI: 10.1038/s41467-018-06958-9

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