Regulation of KRAS-PAK4 axis by microRNAs in cancer

MicroRNAs (miRNAs), often aberrantly expressed in cancer, have been implicated in the regulation of a number of critical cell survival pathways including the genes in the Kras signaling. Kras mutations are observed in more than half of cancers and its inhibition has been the focus of intense research for the past 30 years. However, Kras itself has proven to be non-druggable due in part to the absence of binding pockets for small molecule drugs. These hurdles resulted in researchers shifting their focus on targeting proteins downstream to Kras pathways. P21 activated kinase 4 (PAK4) belongs to the family of serine/threonine kinases comprising of 6 isoforms (PAK 1-6) and is considered as a key effector of Rho family of GTPases downstream of RAS. PAK4 controls critical processes such as cellular motility, proliferation and survival. Recently a number of small molecule PAK4 antagonists have been investigated in preclinical and clinical setting; albeit without any success. Emerging evidence shows that PAK is tightly regulated by a number of miRNAs that are also recognized to promote hyper-activation of oncogenic Kras signaling. Therefore, the understanding of the role of miRNAs in the regulation of PAK4 is critical to the development of therapies against this important player in the Kras pathway. Through this review, we bring forward mechanistic insights on PAK4 regulation by aberrantly expressed miRNAs in cancer and its implications on Kras signaling. We anticipate that enhanced knowledge of the miRNA-PAK4 interaction network will allow the development of successful therapies targeting this critical protein to ultimately rein in Kras.