Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

Abstract

In recent years, a growing number of studies have evaluated the role of exosomes in pancreatic ductal adenocarcinoma cancer (PDAC) demonstrating their involvement in a multitude of pathways, including the induction of chemoresistance. The aim of this review is to present an overview of the current knowledge on the role of exosomes in the resistance to gemcitabine and nab-paclitaxel, which are two of the most commonly used drugs for the treatment of PDAC patients. Exosomes are vesicular cargos that transport multiple miRNAs, mRNAs and proteins from one cell to another cell and some of these factors can influence specific determinants of gemcitabine activity, such as the nucleoside transporter hENT1, or multidrug resistance proteins involved in the resistance to paclitaxel. Additional mechanisms underlying exosome-mediated resistance include the modulation of apoptotic pathways, cellular metabolism, or the modulation of oncogenic miRNA, such as miR-21 and miR-155. The current status of studies on circulating exosomal miRNA and their possible role as biomarkers are also discussed. Finally, we integrated the preclinical data with emerging clinical evidence, showing how the study of exosomes could help to predict the resistance of individual tumors, and guide the clinicians in the selection of innovative therapeutic strategies to overcome drug resistance.

Cancer-Associated Fibroblasts Confer Gemcitabine Resistance to Pancreatic Cancer Cells through PTEN-Targeting miRNAs in Exosomes

“…In addition to PTEN, exosomal miRNAs that target p53 and other genes were recently found to be increased CAFs that were exposed to gemcitabine [ 41 ] or nab paclitaxel [ 42 ]. Because of the overwhelming evidence that cancer cell exosomes promote metastasis [ 43 , 44 ] and drug resistance [ 18 , 40 , 45 ], focus has shifted to testing the use of exosome inhibitors to attenuate metastasis or tumor growth.…”

Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery

“…Although the mechanisms of how it functions have not yet been uncovered, the protein P53 inducible nuclear protein 1 gene is a known tumor suppressor in many different cancers, and its suppression through miR-106b leads to reduced sensitivity to gemcitabine. For pancreatic and ductal adenocarcinoma, gemcitabine resistance is also transferred between the cancer cells via exosomal miR-155 and miR-21 [ 61 , 65 ]. The way miR-155 functions in gemcitabine resistance is by preventing apoptosis through the stimulation of the anti-apoptotic pathway, downregulation of certain tumor suppressor genes such as protein P53 inducible nuclear protein 1 / Sel - 1 - like, and upregulation of genes responsible for exosome synthesis.…”

ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells

“…Paclitaxel also potentiates gemcitabine efficacy by increasing intratumor uptake and inhibiting its inactivation by catabolizing enzymes [ 10 , 11 ]. Mechanisms underlying paclitaxel resistance in PDAC are poorly understood [ 12 , 13 ]. Three studies have investigated paclitaxel resistance in PDAC, reporting that it involves metabolic adaptation [ 14 ], sustained c-MYC activation [ 15 ], and expression of orexin receptor type 1 [ 16 ].…”