Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy

Abstract

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.

Keywords: PDAC; immunotherapy; targeted therapy; treatment.

Figure 1

Shows the initiation and progression of pancreatic cancer. Mutation in oncogenic KRAS is sufficient to initiate the precursor lesion PanIN-1. The accumulation of mutations in the tumor suppressor genes drive PanIN-1 through PanIN-2 and PanIN-3 to PDAC. Alternatively, ductal epithelial cells may malignantly transform through IPMN to PDAC. Overall, the time course between PanIN- 1 and PDAC is more than 30 years. Peters and colleagues reported that progression from PanIN 3 to PDAC took 11.3 years and 12.3 years in men and women, respectively [22].

Figure 2

Shows p53, p16, and p14 tumor suppression pathways and targets of inhibitors.