The therapeutic potential of targeting p21-Activated Kinases (PAK1 – 6) for the treatment of cancer has
recently gained traction in the biotech industry. Many pharmaceutically-viable ATP competitive inhibitors have
been through different stages of pre-clinical development with only a single compound evaluated in human trails
(PF-3758309). The best studied functional roles of PAK proteins are control of cell adhesion and migration. PAK
proteins are known downstream effectors of Ras signaling with PAK expression elevated in cancer (pancreatic,
colon, breast, lung and other solid tumors). In addition altered PAK expression is a confirmed driver of this
disease, especially in tumors harboring oncogenic Ras. However, there are very few examples of gain-of-function
PAK mutations, as a majority of the cancer types have elevated PAK expression due to gene amplification or
transcriptional modifications. There is a substantial number of known substrates affected by this aberrant PAK
activity. One particular substrate, β-catenin, has garnered interest given its importance in both normal and cancer
cell development. These data place PAK proteins between two major signaling pathways in cancer (Ras and β -catenin), making
therapeutic targeting of PAKs an intriguing approach for the treatment of a broad array of oncological malignancies.
Keywords: Inhibitors, oncology, p21-activated kinase, Ras, Wnt; β-catenin.
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