Overcoming drug resistance in pancreatic cancer

Abstract

Introduction: Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies.

Areas covered: Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer and potential strategies to overcome this.

Expert opinion: Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers.

Figure 1. Drug resistance pathways in pancreatic cancer

Drug resistance in pancreatic cancer is caused by various mechanisms including aberrant gene expression, mutations, deregulation of key signaling pathways (such as NF-κB, Notch, Akt, and apoptosis pathways), epithelial-mesenchymal transition (EMT) and the presence of highly resistant cells and stem cells. Each of those mechanisms contributes to drug resistance in pancreatic cancer from different aspects, and suggests different therapeutic targets. A few representative drug resistance pathways such as NF-κB, Notch, Akt, and apoptosis pathways are shown.