ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward?

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.

Keywords: ATP-binding cassette transporters; Multi-drug resistance; Pancreatic ductal adenocarcinoma; Pancreatic ductal adenocarcinoma prognosis; Predictive markers; Targeted therapies.

Figure 1

The schematic presentation of the mechanism of ATP-mediated ATP-binding cassette transporter substrate translocation. TMD: Transmembrane domain; NBD: Nucleotide-binding domain.

Figure 2

Pharmacological approaches towards inhibition of ATP-binding cassette transporters. MDR: Multi-drug resistance; PDAC: Pancreatic ductal adenocarcinoma; ABC: ATP-binding cassette; TK: Tyrosine kinase.