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 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

doi:10.1038/s41467-018-06958-9

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

Nat Commun. 2019 Feb 4;10(1):558. doi: 10.1038/s41467-018-06958-9.

Authors

Yibo Xue^{1

2}, Brian Meehan^{3

4}, Elizabeth Macdonald^{5

6}, Sriram Venneti⁷, Xue Qing D Wang¹, Leora Witkowski^{8

9

10

11}, Petar Jelinic¹², Tim Kong^{1

2}, Daniel Martinez¹³, Geneviève Morin^{1

2}, Michelle Firlit¹², Atefeh Abedini^{5

6}, Radia M Johnson^{1

2}, Regina Cencic^{1

2}, Jay Patibandla¹², Hongbo Chen¹⁴, Andreas I Papadakis^{1

2}, Aurelie Auguste¹⁵, Iris de Rink¹⁶, Ron M Kerkhoven¹⁶, Nicholas Bertos^{1

2}, Walter H Gotlieb¹⁷, Blaise A Clarke¹⁸, Alexandra Leary¹⁵, Michael Witcher^{19

20

21

22}, Marie-Christine Guiot²³, Jerry Pelletier^{1

2}, Josée Dostie¹, Morag Park^{1

2}, Alexander R Judkins²⁴, Ralf Hass²⁵, Douglas A Levine¹², Janusz Rak^{3

4}, Barbara Vanderhyden^{5

6}, William D Foulkes^{26

27

28

29}, Sidong Huang^{30

31}

Affiliations

¹ Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
² The Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada.
³ Department of Pediatrics, McGill University, Montreal, QC, H4A 3J1, Canada.
⁴ Research Institute of McGill University Health Centre Montreal Children's Hospital, Montreal, QC, H4A 3J1, Canada.
⁵ Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1Y 4E9, Canada.
⁶ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
⁷ Pathology and Neuropathology, University of Michigan Medical School, Ann Arbor, MI, 48109-0605, USA.
⁸ Department of Human Genetics, McGill University, Montreal, QC, H3A 0C7, Canada.
⁹ Department of Medical Genetics, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada.
¹⁰ Lady Davis Institute, McGill University, Montreal, QC, H3T 1E2, Canada.
¹¹ Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, H4A 3JI, Canada.
¹² Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, 10016, USA.
¹³ Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA.
¹⁴ School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sat University, 510275, Guangzhou, China.
¹⁵ Department of Cancer Medicine, Gustave Roussy, INSERM U981, 94800, Villejuif, France.
¹⁶ Genomics Core Facility, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
¹⁷ Division of Gynecologic Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada.
¹⁸ Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON, M5G 2C4, Canada.
¹⁹ Department of Oncology, McGill University, Montreal, QC, H3T 1E2, Canada.
²⁰ Department of Experimental Medicine, McGill University, Montreal, QC, H3T 1E2, Canada.
²¹ Lady Davis Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
²² Segal Cancer Centre, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
²³ Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, QC, H3A 2B4, Canada.
²⁴ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, 90027, USA.
²⁵ Biochemistry and Tumor Biology Laboratory, Department of Gynecology and Obstetrics, Medical University Hannover, 30625, Hannover, Germany.
²⁶ Department of Human Genetics, McGill University, Montreal, QC, H3A 0C7, Canada. [email protected].
²⁷ Department of Medical Genetics, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada. [email protected].
²⁸ Lady Davis Institute, McGill University, Montreal, QC, H3T 1E2, Canada. [email protected].
²⁹ Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, H4A 3JI, Canada. [email protected].
³⁰ Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada. [email protected].
³¹ The Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / therapeutic use
Animals
Benzimidazoles / therapeutic use
Carcinoma, Small Cell / drug therapy*
Carcinoma, Small Cell / metabolism*
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Chromatin Immunoprecipitation
Cyclin D1 / deficiency*
Cyclin D1 / metabolism
DNA Helicases / genetics
DNA Helicases / metabolism*
Female
Humans
Hypercalcemia / drug therapy
Hypercalcemia / metabolism
Mice
Mice, SCID
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Ovarian Neoplasms / drug therapy
Ovarian Neoplasms / metabolism
Piperazines / therapeutic use
Protein Kinase Inhibitors / therapeutic use*
Purines / therapeutic use
Pyridines / therapeutic use
RNA, Small Interfering / genetics
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Aminopyridines
Benzimidazoles
Nuclear Proteins
Piperazines
Protein Kinase Inhibitors
Purines
Pyridines
RNA, Small Interfering
Transcription Factors
Cyclin D1
abemaciclib
SMARCA4 protein, human
DNA Helicases
palbociclib
ribociclib

Abstract

Publication types

MeSH terms

Substances

Grants and funding