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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

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

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. More... »

PAGES

558

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-06958-9

    DOI

    http://dx.doi.org/10.1038/s41467-018-06958-9

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111908390

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30718512


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    JSON-LD is a popular format for linked data which is fully compatible with JSON.

    curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s41467-018-06958-9'

    N-Triples is a line-based linked data format ideal for batch operations.

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s41467-018-06958-9'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41467-018-06958-9'

    RDF/XML is a standard XML format for linked data.

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41467-018-06958-9'


     

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    616 https://www.grid.ac/institutes/grid.430814.a schema:alternateName Antoni van Leeuwenhoek Hospital
    617 schema:name Genomics Core Facility, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands
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    619 https://www.grid.ac/institutes/grid.63984.30 schema:alternateName McGill University Health Centre
    620 schema:name Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, H3A 2B4, Montreal, QC, Canada
    621 Department of Pediatrics, McGill University, H4A 3J1, Montreal, QC, Canada
    622 Research Institute of McGill University Health Centre Montreal Children′s Hospital, H4A 3J1, Montreal, QC, Canada
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