Targeting cyclin K in pancreatic cancer

Abstract This study focuses on investigating the role of Cyclin K in pancreatic cancer growth and chemotherapeutic sensitivity, aiming to provide pre-clinical evidence for Cyclin K-targeted therapy in pancreatic cancer. Unlike other well-known cyclins, Cyclin K is largely understudied in cancers. Data extracted from the TCGA database indicated that Cyclin K was overexpressed in pancreatic ductal adenocarcinoma (PDAC) and associated with reduced overall survival. Consistently, western blotting showed that Cyclin K was abundantly expressed in human and mouse PDAC cell lines. By using a Tet-On inducible system, we established Cyclin K-depleted and Cyclin K-overexpressed cell lines to evaluate the function of Cyclin K in pancreatic cancer. The proliferation assay showed that Cyclin K depletion led to retarded PDAC cell proliferation, whereas Cyclin K overexpression boosted cell growth. We further confirmed that Cyclin K was required for pancreatic cancer growth in vivo. In addition, cell cycle analysis showed that Cyclin K deficiency resulted in G1-S arrest, while Cyclin K overexpression promoted G1-S progression. By using an RT2 cell cycler array, we identified CDC20 as an important target of Cyclin K that mediated Cyclin K-induced PDAC cell proliferation. To investigate the influence of Cyclin K on chemo-sensitivity, we treated the PDAC cell lines with two newly synthesized Cyclin K molecular glue degraders (HQ461 and NCT02). We found that these degraders specifically ablated Cyclin K and its cognate kinase CDK12 in a very efficient manner. Importantly, we demonstrated that Cyclin K abrogation, either by Cyclin K degrader or Cyclin K knockdown, rendered PDAC cells more sensitive to GemTaxol (gemcitabine plus Taxol) treatment and PARP inhibitors (olaparib or niraparib), as indicated by increased cleavage of PARP or caspase 3. Together, our current results suggest: 1. Cyclin K promotes cell proliferation and G1-S transition in pancreatic cancer; 2. CDC20 mediates the function of Cyclin K on pancreatic cancer cell proliferation; 3. Cyclin K depletion synergizes with GemTaxol or PARP inhibitor in pancreatic cancer treatment. Our study revealed for the first time that Cyclin K plays an essential role in pancreatic cancer growth and chemo-sensitivity, and targeting Cyclin K may offer a great therapeutic avenue for pancreatic cancer patients. Citation Format: Yi Xiao, Jixin Dong, Yuanhong Chen. Targeting cyclin K in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3932.