Molecular pathways: targeting RAC-p21-activated serine-threonine kinase signaling in RAS-driven cancers

Abstract

Cancers driven by oncogenic Ras proteins encompass some of the most deadly human cancer types, and there is a pressing need to develop therapies for these diseases. Although recent studies suggest that mutant Ras proteins may yet be druggable, the most promising and advanced efforts involve inhibitors of Ras effector signaling. Most efforts to target Ras signaling have been aimed at the ERK mitogen-activated protein kinase and the phosphoinositide 3-kinase signaling networks. However, to date, no inhibitors of these Ras effector pathways have been effective against RAS-mutant cancers. This ineffectiveness is due, in part, to the involvement of additional effectors in Ras-dependent cancer growth, such as the Rac small GTPase and the p21-activated serine-threonine kinases (PAK). PAK proteins are involved in many survival, cell motility, and proliferative pathways in the cell and may present a viable new target in Ras-driven cancers. In this review, we address the role and therapeutic potential of Rac and group I PAK proteins in driving mutant Ras cancers.

Figure 1

Ras effector signaling. The importance of the Raf-MEK-ERK and PI3K-AKT-mTOR effector signaling networks are well validated drivers of mutant Ras-dependent cancer growth. Rac is activated by Ras through direct (e.g., Tiam1) or indirect (via PIP3 formation) activation of guanine nucleotide exchange factors for the Rac small GTPase. The group I PAKs comprise one key effector family of Rac. Over 50 substrates of PAK1 have been described (compiled from references and 39). These substrates include components of the ERK MAPK cascade. PAK1 can also function as a scaffold to facilitate AKT activation.