Abstract 1379 CDK1-SOX9 axis contributes to chemotherapy resistance in gastric cancer

Gastric carcinoma (GC) is the third most prevalent cause of cancer-related mortality worldwide, presenting a formidable challenge with the rise of resistance to chemotherapeutic agents, leading to treatment failures. Cyclin-dependent kinase 1 (CDK1) has garnered attention due to its substantial overexpression in various tumors, including GC, and its association with poor overall survival and relapse-free survival. This study aimed to understand the molecular and functional mechanisms underlying the CDK1-SOX9 axis in GC chemotherapy resistance. Through a comprehensive analysis of data from The Cancer Genome Atlas (TCGA) and our own integrated gene expression study, we found a positive correlation between CDK1 and SOX9 in both human and mouse GC tissues (p<0.001). Additionally, conserved alterations in miRNAs have been identified in the context of gastric carcinogenesis, evident in our local cohort and the TCGA dataset. Our in-depth investigation of premiR-145 has shed light on the existence of several CpG nucleotides. Notably, treatment with a DNMT inhibitor (5-Aza) has triggered the upregulation of miR-145 expression. Furthermore, the ectopic expression of CDK1 has been associated with increased DNMT1 phosphorylation and enhanced enzymatic activity. Conversely, silencing CDK1 reversed this effect, and the inhibition of DNMT1 reduced SOX9 protein expression. Using cisplatin-resistant cell lines revealed a significant increase in CDK1 and SOX9 expression where silencing CDK1 and SOX9 sensitized these cells to chemotherapy. This study provides valuable insights into the intricate mechanisms governing the CDK1-SOX9 axis in GC chemotherapy resistance, providing potential avenues for therapeutic interventions in this challenging malignancy. This study is supported by US NIH funding (R01CA249949) and Department of Veterans Affairs awards (1IK6BX003787 and I01BX001179). The use of shared resources is supported by the National Cancer Institute-funded Sylvester Comprehensive Cancer Center P30CA240139.