Novel TRAIL-based therapies for pancreatic cancer

Abstract

Background: Prognosis of pancreatic cancer remains poor. Therefore novel therapeutic strategies are urgently needed. TRAIL can induce apoptosis in cancer cells. However, TRAIL has only shown limited therapeutic benefit in patients. Consequently, TRAIL-based therapies will require the addition of TRAIL-sensitizing agents. Methods: Tumor and normal tissue of pancreatic cancer patients was analyzed for CDK9 expression and correlated with patients' survival. Moreover, the therapeutic potential of a selective CDK9-inhibitor on pancreatic cancer cells was evaluated alone and in combination with TRAIL by analysis of cell viability, long-term survival and apoptosis and characterized using western blotting and flow cytometry. Results: Here, we identify CDK9 as an extremely potent TRAIL-sensitizing strategy in pancreatic cancer. CDK9 is overexpressed in pancreatic cancer tissue. In addition high CDK9 expression in tumor tissue is associated with significantly shortened survival. Pharmacological CDK9-inhibition in combination with TRAIL potently and rapidly reduced cell viability in pancreatic cancer cells, potently suppressed long-term survival and induced cell death. Analyzing the molecular mechanism revealed that CDK9-inhibition sensitized to TRAIL-induced apoptosis by suppression of important anti-apoptotic proteins. Conclusion: Based on the high potency of CDK9-inhibition as a TRAIL-sensitizing strategy, we envisage the development of new, highly effective cancer therapies for pancreatic cancer.