TY - JOUR
T1 - Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
AU - Howard, David
AU - James, David
AU - Garcia-Parra, Jezabel
AU - Pan-Castillo, Belen
AU - Worthington, Jenny
AU - Williams, Nicole
AU - Coombes, Zoe
AU - Rees, Sophie Colleen
AU - Lutchman-Singh, Kerryn
AU - Francis, Lewis W.
AU - Rees, Paul
AU - Margarit, Lavinia
AU - Conlan, R. Steven
AU - Gonzalez, Deyarina
N1 - Funding Information:
This work was funded by Tenovus Cancer Care (grant no. PhD2015/L35), the Life Science National Research Network in Drug Discovery (2016/BPC) and Welsh Government ERDF SMART Expertise 2014-2020 West Wales and the Valleys (2017/COL/001 and 2017/COL/004).
Publisher Copyright:
Copyright © 2022 Howard, James, Garcia-Parra, Pan-Castillo, Worthington, Williams, Coombes, Rees, Lutchman-Singh, Francis, Rees, Margarit, Conlan and Gonzalez.
PY - 2022/11/25
Y1 - 2022/11/25
N2 - Background: Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC. Aim: The aim of this study was to evaluate the efficacy of CDKis in platinum resistant OC models and serve as a predictor of potential clinical utility. Methods: The efficacy of CDKi, dinaciclib, was determined in wildtype and platinum resistant cell line pairs representing different OC subtypes. In addition, dinaciclib was evaluated in primary cells isolated from platinum-sensitive and platinum-refractory tumors to increase the clinical relevance of the study. Results and conclusions: Dinaciclib proved highly efficacious in OC cell lines and primary cells, which were over a thousand-fold more sensitive to the CDKi than to cisplatin. Furthermore, cisplatin resistance in these cells did not influence sensitivity to dinaciclib and the two drugs combined additively in both platinum-sensitive and platinum-resistant OC cells suggesting a potential role for pan-CDKis (CDKis targeting multiple CDKs), such as dinaciclib, in the treatment of advanced and platinum-resistant OC.
AB - Background: Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC. Aim: The aim of this study was to evaluate the efficacy of CDKis in platinum resistant OC models and serve as a predictor of potential clinical utility. Methods: The efficacy of CDKi, dinaciclib, was determined in wildtype and platinum resistant cell line pairs representing different OC subtypes. In addition, dinaciclib was evaluated in primary cells isolated from platinum-sensitive and platinum-refractory tumors to increase the clinical relevance of the study. Results and conclusions: Dinaciclib proved highly efficacious in OC cell lines and primary cells, which were over a thousand-fold more sensitive to the CDKi than to cisplatin. Furthermore, cisplatin resistance in these cells did not influence sensitivity to dinaciclib and the two drugs combined additively in both platinum-sensitive and platinum-resistant OC cells suggesting a potential role for pan-CDKis (CDKis targeting multiple CDKs), such as dinaciclib, in the treatment of advanced and platinum-resistant OC.
KW - cisplatin
KW - cyclin dependent kinase inhibitor
KW - dinaciclib
KW - flavopiridol
KW - ovarian cancer
KW - platinum
KW - refractory
KW - resistance
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U2 - 10.3389/fonc.2022.1014280
DO - 10.3389/fonc.2022.1014280
M3 - Article
C2 - 36505806
AN - SCOPUS:85143749574
SN - 2234-943X
VL - 12
SP - 1014280
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1014280
ER -