CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 04, 2019
- Source ID
- 10.1038/s41467-018-06958-9
Entities
People
- Alexander R. Judkins
- Alexandra Leary
- Andreas I. Papadakis
- Atefeh Abedini
- Aurelie Auguste
- Barbara Vanderhyden
- Blaise A. Clarke
- Brian Meehan
- Daniel Martinez
- Douglas A Levine
- Elizabeth A MacDonald
- Geneviève Morin
- Hongbo Chen
- Iris De Rink
- Janusz Rak
- Jay Patibandla
- Jerry Pelletier
- Josée Dostie
- Leora Witkowski
- Marie-christine Guiot
- Michael Witcher
- Michelle Firlit
- Morag Park
- Nicholas Bertos
- Petar Jelinic
- Radia M. Johnson
- Ralf Hass
- Regina Cencic
- Ron M. Kerkhoven
- Sidong Huang
- Sriram Venneti
- Tim Kong
- Walter H. Gotlieb
- William David Foulkes
- Xue Qing D. Wang
- Yibo Xue
Organizations
- Canadian HIV Trials Network, Canadian Institutes of Health Research
- Canadian Institutes of Health Research
- Congressionally Directed Medical Research Programs