Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2018; 24(33): 3709-3723
Published online Sep 7, 2018. doi: 10.3748/wjg.v24.i33.3709
p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation
Kai Wang, Graham S Baldwin, Mehrdad Nikfarjam, Hong He
Kai Wang, Graham S Baldwin, Mehrdad Nikfarjam, Hong He, Department of Surgery, University of Melbourne, Melbourne 3084, Australia
Author contributions: Wang K reviewed the literature and drafted the manuscript; He H, Baldwin GS and Nikfarjam M revised the manuscript; all authors approved the final version of this review.
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: 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:
Correspondence to: Hong He, MD, PhD, Senior Research Fellow, Department of Surgery, University of Melbourne, Austin Health, 145 Studley Rd., Heidelberg 3084, Victoria, Australia.
Telephone: +61-3-94965468
Received: May 22, 2018
Peer-review started: May 23, 2018
First decision: June 11, 2018
Revised: June 22, 2018
Accepted: June 27, 2018
Article in press: June 27, 2018
Published online: September 7, 2018

Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.

Keywords: Pancreatic cancer, Kras, p21-activated kinases, Cell signalling, Chemo-resistance, Immune response, Tumour microenvironment

Core tip: Pancreatic cancer is still one of the most lethal malignancies, with a five-year survival of less than 8%. The dismal prognosis is largely the result of reprogramming of the tumour microenvironment, which leads to chemo-resistance and high aggressiveness. So far, combination chemotherapies can only marginally improve patients’ survival, but with high toxicity. Therefore, alternative treatment targeting protein kinase signalling has been proposed. As downstream effectors of Kras signalling, p21-activated kinases (PAKs) are positioned at the nexus of multiple oncogenic signalling pathways. Here, the importance of PAKs as therapeutic targets in Kras signalling is discussed, and their essential role in tumour biology and immune modulation within the tumour microenvironment is highlighted.