p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

World J Gastroenterol. 2018 Sep 7;24(33):3709-3723. doi: 10.3748/wjg.v24.i33.3709.

Abstract

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

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / immunology
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / immunology
  • Humans
  • Immunotherapy / methods*
  • Molecular Targeted Therapy / methods
  • Mutation
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / mortality
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • p21-Activated Kinases / antagonists & inhibitors
  • p21-Activated Kinases / immunology
  • p21-Activated Kinases / metabolism*

Substances

  • Antineoplastic Agents, Immunological
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • p21-Activated Kinases
  • Proto-Oncogene Proteins p21(ras)