Abstract
Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum-based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum-treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.
| Original language | English |
|---|---|
| Pages (from-to) | 1415-1433 |
| Number of pages | 19 |
| Journal | EMBO Molecular Medicine |
| Volume | 9 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Oct 2017 |
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- Journal Article
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CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation. / Dall'Acqua, Alessandra; Sonego, Maura; Pellizzari, Ilenia; Pellarin, Ilenia; Canzonieri, Vincenzo; D'Andrea, Sara; Benevol, Sara; Sorio, Roberto; Giorda, Giorgio; Califano, Daniela; Bagnoli, Marina; Militello, Loredana; Mezzanzanica, Delia; Chiappetta, Gennaro; Armenia, Joshua; Belletti, Barbara; Schiappacassi, Monica; Baldassarre, Gustavo.
In: EMBO Molecular Medicine, Vol. 9, No. 10, 10.2017, p. 1415-1433.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation
AU - Dall'Acqua, Alessandra
AU - Sonego, Maura
AU - Pellizzari, Ilenia
AU - Pellarin, Ilenia
AU - Canzonieri, Vincenzo
AU - D'Andrea, Sara
AU - Benevol, Sara
AU - Sorio, Roberto
AU - Giorda, Giorgio
AU - Califano, Daniela
AU - Bagnoli, Marina
AU - Militello, Loredana
AU - Mezzanzanica, Delia
AU - Chiappetta, Gennaro
AU - Armenia, Joshua
AU - Belletti, Barbara
AU - Schiappacassi, Monica
AU - Baldassarre, Gustavo
N1 - © 2017 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2017/10
Y1 - 2017/10
N2 - Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum-based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum-treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.
AB - Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum-based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum-treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.
KW - Journal Article
U2 - 10.15252/emmm.201607012
DO - 10.15252/emmm.201607012
M3 - Article
C2 - 28778953
VL - 9
SP - 1415
EP - 1433
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 10
ER -