Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer

• DOI: 10.3389/fonc.2022.1014280
• Publication Date: 2022-11-25T06:23:10Z
• Authors: David Howard; David James; Jezabel Garcia-Parra; Belen Pan-Castillo; Jenny Worthington; Nicole Williams; Zoe Coombes; Sophie Colleen Rees; Kerryn Lutchman-S...; Lewis W. Francis; Paul Rees; Lavinia Margarit; R. Steven Conlan; Deyarina Gonzalez
• Keywords: 610; cyclin dependent kinase inhibitor; dinaciclib; cisplatin; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; 3. Good health; resistance; 03 medical and health sciences; ovarian cancer; 0302 clinical medicine; Oncology; platinum; RC254-282

Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking specific symptoms early stages, OC predominantly diagnosed late when disease has undergone metastatic spread and chemotherapy relied on to prolong life. Platinum-based therapies are preferred although many tumors respond initially, emergence platinum-resistance occurs majority cases after which prognosis very poor. Upregulation DNA damage pathways a feature platinum resistance with cyclin dependent kinases (CDKs) serving as key regulators this process suggesting that CDK inhibitors (CDKis) could be effective tools treatment resistant refractory OC.The aim study was evaluate efficacy CDKis models serve predictor potential clinical utility.The CDKi, dinaciclib, determined wildtype cell line pairs representing different subtypes. In addition, dinaciclib evaluated primary cells isolated from platinum-sensitive platinum-refractory increase relevance study.Dinaciclib proved highly efficacious lines cells, were over thousand-fold more sensitive CDKi than cisplatin. Furthermore, cisplatin these did not influence sensitivity two drugs combined additively both platinum-resistant role for pan-CDKis (CDKis targeting multiple CDKs), such advanced OC.