Reviews:
Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer?
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Abstract
Kiruthikah Thillai1,2,*, Hoyin Lam1,*, Debashis Sarker1,2 and Claire M. Wells1
1 Division of Cancer Studies, King’s College London, London, United Kingdom
2 Department of Medical Oncology, Guy’s and St Thomas’ NHS Trust, London, United Kingdom
* Both authors have contributed equally to this work
Correspondence to:
Claire M. Wells, email:
Keywords: pancreatic cancer, PAK, PI3K
Received: July 29, 2016 Accepted: October 27, 2016 Published: November 11, 2016
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.
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PII: 13309