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

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

Nature communications, 2019-02, Vol.10 (1), p.558-15, Article 558 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary
Autor: Xue, Yibo ; Meehan, Brian ; Macdonald, Elizabeth ; Venneti, Sriram ; Wang, Xue Qing D ; Witkowski, Leora ; Jelinic, Petar ; Kong, Tim ; Martinez, Daniel ; Morin, Geneviève ; Firlit, Michelle ; Abedini, Atefeh ; Johnson, Radia M ; Cencic, Regina ; Patibandla, Jay ; Chen, Hongbo ; Papadakis, Andreas I ; Auguste, Aurelie ; de Rink, Iris ; Kerkhoven, Ron M ; Bertos, Nicholas ; Gotlieb, Walter H ; Clarke, Blaise A ; Leary, Alexandra ; Witcher, Michael ; Guiot, Marie-Christine ; Pelletier, Jerry ; Dostie, Josée ; Park, Morag ; Judkins, Alexander R ; Hass, Ralf ; Levine, Douglas A ; Rak, Janusz ; Vanderhyden, Barbara ; Foulkes, William D ; Huang, Sidong
Assuntos: Aminopyridines - therapeutic use ; Animals ; Benzimidazoles - therapeutic use ; Breast cancer ; BRG1 protein ; Carcinoma, Small Cell - drug therapy ; Carcinoma, Small Cell - metabolism ; Cell Line, Tumor ; Cell Survival - drug effects ; Cell Survival - genetics ; Chromatin Immunoprecipitation ; Chromatin remodeling ; Cyclin D1 ; Cyclin D1 - deficiency ; Cyclin D1 - metabolism ; Cyclin-dependent kinase 4 ; Cyclin-dependent kinases ; DNA Helicases - genetics ; DNA Helicases - metabolism ; Female ; Humans ; Hypercalcemia ; Hypercalcemia - drug therapy ; Hypercalcemia - metabolism ; Inhibitors ; INK4a protein ; Kinases ; Mice ; Mice, SCID ; Mutation ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - metabolism ; p16 Protein ; Piperazines - therapeutic use ; Protein Kinase Inhibitors - therapeutic use ; Purines - therapeutic use ; Pyridines - therapeutic use ; Retinoblastoma ; RNA, Small Interfering - genetics ; RNA-mediated interference ; Screens ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor suppressor genes ; Tumors
É parte de: Nature communications, 2019-02, Vol.10 (1), p.558-15, Article 558
Descrição: 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 -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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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