Abstract 5416: Cyclin K deficiency suppresses tumor growth, activates systemic immunity, and confers vulnerability to chemotherapy in pancreatic cancer

Abstract Pancreatic cancer is a highly lethal disease worldwide, therefore, it is imperative to identify critical targets to inform alternative therapeutics in this disease. Cyclins and cyclin-dependent kinases (CDKs) are key drivers in the hallmarks of cancer, and important targets in clinical trials and cancer treatment. Proven as a druggable target in recent years, however, the function of Cyclin K in pancreatic cancer is still unknown. This study characterizes the role of Cyclin K in tumorigenesis, systemic immunity, and GemTaxol (gemcitabine and paclitaxel) sensitivity in pancreatic cancer, aiming to provide a pre-clinical basis for Cyclin K-targeted therapies in this disease. Data from TCGA and GTEx indicated that Cyclin K expression was high in pancreatic tumors, and elevated expression of Cyclin K was associated with shorter survival. Consistent with this finding, transgenic mouse models suggested Cyclin K expression was induced in KPC (KrasG12D; Trp53flox/flox; Pdx1-Cre) tumors, whereas homozygous deletion of Cyclin K in KPC mice (KrasG12D; Trp53flox/flox; Pdx1-Cre; Ccnkflox/flox) offered survival benefit. Next, Cyclin K expression was depleted in pancreatic ductal adenocarcinoma (PDAC) cells to investigate the gene function. Inducible knockdown of Cyclin K restricted proliferation and G1-S transition of PDAC cells, while enhanced expression of Cyclin K promoted cell proliferation and cell cycle progression. Cell division cycle 20 (CDC20) was identified by a cell cycle array to mediate Cyclin K-induced cell proliferation. The loss of Cyclin K also hampered PDAC tumor growth in athymic nude mice. Interestingly, in immunocompetent mice, Cyclin K depletion not only attenuated tumor growth, but also led to some levels of complete tumor regression. Cyclin K deficiency-triggered systemic immunity was further examined by rechallenging the tumor-cleared mice with control murine cancer cells. As a result, the tumor clearance rate is 100% in these immunized mice. In addition, RNA-Seq identified immune response and inflammatory response to be the top 10 significantly altered gene ontology terms in Cyclin K-knockdown cells. Importantly, genetic depletion of Cyclin K synergized with GemTaxol to restrain PDAC tumor growth. Furthermore, the combination of GemTaxol and Cyclin K depletion, either by genetic or pharmaceutical methods, markedly induced apoptosis in cells. Finally, two PROTAC degraders (7f and YJ9069) were shown to exert significant anti-tumor growth effect in immunocompetent mice. Together, this work highlights that Cyclin K is a master regulator of tumor growth, immune response, and chemoresistance in PDAC, and a promising target for the treatment of pancreatic cancer. Citation Format: Yi Xiao, Yuanhong Chen, Jixin Dong. Cyclin K deficiency suppresses tumor growth, activates systemic immunity, and confers vulnerability to chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5416.