The challenge of drug resistance in pancreatic ductal adenocarcinoma: a current overview

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among all cancer types. Its delayed diagnosis precludes curative resection, thus most of the current therapies against PDAC are based on chemo- and radiotherapy. Unfortunately, these strategies are insufficient to improve its poor prognosis. Despite the advances made in chemotherapy (e.g. nab-paclitaxel and gemcitabine), many patients with PDAC are unable to benefit from them due to the rapid development of drug resistance. Currently, more than 165 genes have been found to be implicated in drug resistance of pancreatic tumors, including different integrins, mucins, NF-κB, RAS and CXCR4. Moreover, drug resistance in PDAC is thought to be mediated by the modulation of miRNAs (e.g. miRNA-21, miRNA-145 and miRNA-155), which regulate genes that participate in cell proliferation, invasion and metastasis. Finally, cancer stem cells are intimately related to drug resistance in PDAC due to their ability to overexpress ABC genes -involved in drug transport-, and enzymes such as aldehyde dehydrogenases -implicated in cellular drug metabolism- and poly (ADP-ribose) polymerases -involved in drug-induced DNA damage repair. Understanding the mechanisms involved in drug resistance will contribute to the development of efficient therapeutic strategies and to improve the prognosis of patients with PDAC.

Keywords: Pancreatic ductal adenocarcinoma; cancer stem cells; chemotherapy; drug resistance; therapeutic strategies.

1. Different mechanisms of drug resistance in pancreatic cancer deregulated molecular signal pathways such as RAS, NFκB and PI3K pathways and, overcoat KRAS and BRCA genetic deregulation. These mechanisms comprise that tissular hypoxia increases HIF-1 levels and diminishes reactive oxygen species (ROS), a dense extracellular matrix impedes the diffusion of chemotherapeutic agents, and the existence of cancer stem cells escape to apoptosis.

2. ABC transporters in detoxification of chemotherapeutic drugs in pancreatic cancer. The most common drugs are oxaliplatin (OXA), 5-fluorouracil (5-FU), gemcitabine (GEM), irinotecan (IRI) and Nab-paclitaxel (Nab-PTX). The main ABC transporters (ATP binding cassette) in pancreatic cancer was breast cancer resistant protein (BCRP), P- glycoprotein (P-gp) and multidrug resistance protein (MRP). MRP and BCRP transporters require the conjugation with glutathione.

3. Mechanism of action of PARP (poly-ADP-ribose-polymerase). Single strand DNA damage induced by chemotherapeutic agents or radiotherapy is repaired by this enzyme leading to cell survival. In this process PARP accumulates ADP tails. However, big amounts of DNA damage cannot be repaired by PARP, so that, ADP tails are released and induce cell death (A). Mechanism of synthetic lethality. BER Base Excision Repair (RES) system repairs single chain DNA damage and Homologous recombination system (HRS) repair double strand DNA damage. These two systems are consecutive, so that, DNA damage and the ineffective of BER lead to the activation of HRS. HRS is made up by repair proteins like BRCA, ATM or ATR. Germinal of somatical mutations in these genes provoke an ineffective HRS dependent DNA repair. This fact could profit to trigger a syntetic lethality, inhibiting PARP with molecules such as olaparib. Therefore, the deffective HRS due to genetic mutations added to BER system inhibition by PARP blockers lead to apoptosis of cancer cells (B).