Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27(39): 6527-6550 [PMID: 34754151 DOI: 10.3748/wjg.v27.i39.6527]
Corresponding Author of This Article
Vikas Bhardwaj, PhD, Assistant Professor, Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, 130 South 9th Street, Philadelphia, PA 19107, United States. vikas.bhardwaj@jefferson.edu
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Oct 21, 2021; 27(39): 6527-6550 Published online Oct 21, 2021. doi: 10.3748/wjg.v27.i39.6527
Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities
Aditi Jain, Vikas Bhardwaj
Aditi Jain, The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
Vikas Bhardwaj, Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
Author contributions: Jain A and Bhardwaj V decided on topics, compiled information, wrote and reviewed the manuscript.
Conflict-of-interest statement: The authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Vikas Bhardwaj, PhD, Assistant Professor, Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, 130 South 9th Street, Philadelphia, PA 19107, United States. vikas.bhardwaj@jefferson.edu
Received: May 6, 2021 Peer-review started: May 6, 2021 First decision: June 12, 2021 Revised: June 22, 2021 Accepted: August 30, 2021 Article in press: August 30, 2021 Published online: October 21, 2021 Processing time: 166 Days and 11.4 Hours
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor’s immunological response.
Core Tip: With a five-year survival rate of 10%, pancreatic adenocarcinomas are one of the most aggressive forms of cancer. Despite extensive efforts, only a few drug combinations have been found to be effective in improving patient outcomes. The drug-resistant mechanisms active in pancreatic ductal adenocarcinoma contribute to the ineffectiveness of therapies. Through this review, we discuss key mechanisms that contribute to the development of resistant phenotype in pancreatic tumors and how these mechanisms are being sought as a target to treat this cancer.
