Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer

Abstract

Metastatic prostate cancer (mPCa) has limited therapeutic options and a high mortality rate. The p21-activated kinase (PAK) family of proteins is important in cell survival, proliferation, and motility in physiology, and pathologies such as infectious, inflammatory, vascular, and neurological diseases as well as cancers. Group-I PAKs (PAK1, PAK2, and PAK3) are involved in the regulation of actin dynamics and thus are integral for cell morphology, adhesion to the extracellular matrix, and cell motility. They also play prominent roles in cell survival and proliferation. These properties make group-I PAKs a potentially important target for cancer therapy. In contrast to normal prostate and prostatic epithelial cells, group-I PAKs are highly expressed in mPCA and PCa tissue. Importantly, the expression of group-I PAKs is proportional to the Gleason score of the patients. While several compounds have been identified that target group-I PAKs and these are active in cells and mice, and while some inhibitors have entered human trials, as of yet, none have been FDA-approved. Probable reasons for this lack of translation include issues related to selectivity, specificity, stability, and efficacy resulting in side effects and/or lack of efficacy. In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline.

The Histogenetic Origin of Malignant Cells Predicts Their Susceptibility towards Synthetic Lethality Utilizing the TK.007 System

“…Another interesting protein in this context is PAK1, which interacts with CTNNB1 and has already been described as a potential target for prostate cancer [ 15 ].…”

PAK1 and Therapy Resistance in Melanoma

“…While their Activated PAK1 is known to phosphorylate a great number of targets. While their complete inventory is beyond the scope of this review, the numerous biochemical and biological consequences of PAK1 activity have been extensively reviewed elsewhere [28,[37][38][39][40]. The involvement of many of the PAK1-regulated factors in such phenomena as cell motility, cell proliferation, and survival support the continuous interest in PAK1 among cancer researchers and has led to the recognition of this enzyme as a bona fide target for anticancer therapy [28].…”

“…To date, there is a multitude of chemical agents that can inhibit this enzyme, yet none have received an approval for clinical use. The histories, chemical structures, specificities, and investigational status of these molecules have been extensively reviewed by others elsewhere [39,40,144]. The hurdles for the currently available compounds range from chemical instability and poor bioavailability to off-target effects and expected toxicity.…”