Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer?

Abstract

The development of personalised therapies has ushered in a new and exciting era of cancer treatment for a variety of solid malignancies. Yet pancreatic ductal adenocarcinoma (PDAC) has failed to benefit from this paradigm shift, remaining notoriously refractory to targeted therapies. Chemotherapy is the cornerstone of management but can offer only modest survival benefits of a few months with 5-year survival rates rarely exceeding 3%. Despite these disappointing statistics, significant strides have been made towards understanding the complex biology of pancreatic cancer, with deep genomic sequencing identifying novel genetic aberrations and key signalling pathways. The PI3K-PDK1-AKT pathway has received great attention due to its prominence in carcinogenesis. However, efforts to target several components of this network have resulted in only a handful of drugs demonstrating any survival benefit in solid tumors; despite promising pre-clinical results. p-21 activated kinase 4 (PAK4) is a gene that is recurrently amplified or overexpressed in PDAC and both PAK4 and related family member PAK1, have been linked to aberrant RAS activity, a common feature in pancreatic cancer. As regulators of PI3K, PAKs have been highlighted as a potential prognostic marker and therapeutic target. In this review, we discuss the biology of pancreatic cancer and the close interaction between PAKs and the PI3K pathway. We also suggest proposals for future research that may see the development of effective targeted therapies that could finally improve outcomes for this disease.

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

“…Several studies have highlighted the role of PAK in the phosphorylation of both RAF-1 and MEK, facilitating signaling through the RAS/RAF/MAPK pathway 37 38 . On the other hand, PAK is a key mediator in the PI3K-AKT signaling axis through AKT phosphorylation on S473 and T308; furthermore, PAK could be directly activated by PI3K via RAC1/Cdc45 39 40 . Activation of the transcription factor NFκB appears to be a prominent mechanism by which PAK1 potentially regulates survival of cancer cells 40 41 ; consistent with the hypothesis that combined MEK/mTOR inhibition in PTEN-loss contexts might synergistically inhibit tumor growth by selectively modulating a PAK/NFκB axis.…”

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…The PI3K-Akt-mTOR pathway is also responsible for controlling cellular metabolism. The PI3K/Akt pathway can also inhibit glucose metabolism by blocking glycogen synthase kinase 3b and can alter glucose uptake by mediating expression of glucose transporters such as GLUT1 [105,106]. The PI3K/Akt pathway can also inhibit glucose metabolism by blocking glycogen synthase kinase 3b and can alter glucose uptake by mediating expression of glucose transporters such as GLUT1 [105,106].…”

“…Oncogenic K-Ras can enhance the activity of the metabolic enzyme ATP citrate lyase in an Aktdependent manner leading to histone acetylation and alteration of the acetyl-CoA pool, subsequently leading to changes in gene expression, DNA damage response and DNA replication [105]. The PI3K/Akt pathway can also inhibit glucose metabolism by blocking glycogen synthase kinase 3b and can alter glucose uptake by mediating expression of glucose transporters such as GLUT1 [105,106]. Furthermore, Akt signalling is present in preneoplastic lesions during pancreatic carcinogenesis induced by mutated Kras, and is associated with progression towards higher grade tumours and poorer patient survival [99,[107][108][109].…”

Role of Phosphoinositides in Cellular Signaling, Functions and Diseases

“…PDK1 activates Akt by phosphorylation of threonine site. Overexpression of PAK, which is one of the downstream effectors of PIP3, is correlated with many cancer types such as ovarian cancer 80,106 . PI3K catalyzes PIP2 into PIP3 107 (figure5).…”

“…PI3K catalyzes PIP2 into PIP3 107 (figure5). One of the major downstream effectors of Akt is mTORc1 which is deregulated in many cancers when phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene dephosphorylates PIP3 to PIP2 106 .…”