CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

Abstract

Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.