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

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.

Figure 1

Structure of p21-activated kinases. The six members of the PAK family can be divided by sequence and structural differences into two groups: Group I (PAK1-3) and group II (PAK4-6). All PAKs have an N-terminal regulatory domain and a conserved C-terminal serine/threonine kinase domain. In group I PAKs, the regulatory domain contains an AID, whereas group II PAKs (with the possible exception of PAK5) do not have a well-defined AID, but instead an AID-like domain. PIX: PAK-interactive exchange factor; PAK: p21-activated kinases; AID: Autoinhibitory domain; GBD: GTPase-binding domain.

Figure 2

Role of p21-activated kinases in Kras-driven oncogenic signalling pathways. Rac1 is the 4^th best validated effector in Kras signalling and is a well-defined upstream protein of PAKs. Rac1 plays an important role in the ADM/PanIN/PDAC transition. In addition, Rac1/Cdc42 mediates this pathological process via the PI3K-PDK1 signalling pathway. PDK1 can also interact with PAK1, leading to its phosphorylation. The Kras oncogene activates PAKs through direct and indirect pathways. Activated PAKs can increase cancer cell proliferation, migration and survival through activation of AKT, Crk and RAF-MEK-ERK pathways. PAK: p21-activated kinases; ADM: Acinar-ductal metaplasia; PDAC: Pancreatic ductal adenocarcinoma; PDK1: Phosphoinositide-dependent kinase-1.

Figure 3

p21-activated kinases signalling in the development of pancreatic cancer. PAK signalling is involved in several pathobiological processes in pancreatic cancer, including proliferation, migration/invasion, apoptosis and maintenance of stem cell-like properties. Amplification of the PAK1 and PAK4 genes, present within the chromosomal regions 11q13 and 19q13.2, respectively, has been observed. Activated PAK1 regulates cell transformation and the invasive EMT phenotype of pancreatic cancer cells via the NF-κB-p65-fibronectin axis. Additionally, MUC13 promotes cancer cell growth and invasion/migration, and reduces animal survival, by up-regulating expression and phosphorylation of PAK1. Furthermore, PAK4 modulates proliferation and survival by mediating the activity of NF-κB via AKT- and ERK-dependent pathways, and cancer stem cell-like properties via STAT3 signalling. Pharmacological or genetic inhibition of PAK1 or PAK4 leads to decreased cancer cell proliferation, invasion/migration and PSC activation in vitro, and reduced tumour growth and metastasis, and increased animal survival in vivo. PAK: p21-activated kinases; PSC: Pancreatic stellate cells.