TY - JOUR
T1 - CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary
AU - Xue, Yibo
AU - Meehan, Brian
AU - Macdonald, Elizabeth
AU - Venneti, Sriram
AU - Wang, Xue Qing D.
AU - Witkowski, Leora
AU - Jelinic, Petar
AU - Kong, Tim
AU - Martinez, Daniel
AU - Morin, Geneviève
AU - Firlit, Michelle
AU - Abedini, Atefeh
AU - Johnson, Radia M.
AU - Cencic, Regina
AU - Patibandla, Jay
AU - Chen, Hongbo
AU - Papadakis, Andreas I.
AU - Auguste, Aurelie
AU - de Rink, Iris
AU - Kerkhoven, Ron M.
AU - Bertos, Nicholas
AU - Gotlieb, Walter H.
AU - Clarke, Blaise A.
AU - Leary, Alexandra
AU - Witcher, Michael
AU - Guiot, Marie Christine
AU - Pelletier, Jerry
AU - Dostie, Josée
AU - Park, Morag
AU - Judkins, Alexander R.
AU - Hass, Ralf
AU - Levine, Douglas A.
AU - Rak, Janusz
AU - Vanderhyden, Barbara
AU - Foulkes, William D.
AU - Huang, Sidong
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061048478&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06958-9
DO - 10.1038/s41467-018-06958-9
M3 - Article
C2 - 30718512
AN - SCOPUS:85061048478
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 558
ER -