Background: The frequency of pro-oncogenic mutations and development of
drug resistance are major challenges for successful Ras-related cancer treatment. Novel targets
in the Ras-signaling pathway may address these challenges. Cell division cycle protein
42 (Cdc42) is a classical member of the Rho family of small GTPases in the Ras oncogene
superfamily. Enhanced Cdc42-signaling facilitates Ras-mediated cellular transformation,
tumorigenesis, and metastasis. Cdc42, Ras, and EGFR are involved in an activation loop
that prolongs their signaling. This review evaluates the benefits of targeting Cdc42 signaling
as an anti-Ras cancer target.
Methods: We review the link between Ras and Cdc42 and summarize the roles of Cdc42
and select effectors in cancers. We discuss the discovery/development of Cdc42-signaling
modulators and highlight studies that report the inhibition of the Cdc42-signaling pathway
in several Ras-related cancer cell lines.
Results: Compared to EGFR and Ras, mutations that lead to the prolonged activation of
Cdc42 are less common. Activation of upstream signals, changes in regulator expression,
and alterations of Cdc42 protein expression play an important role in regulating Cdc42 activity.
Eight selected effectors/adaptors of Cdc42 play a role in oncogenic Ras signaling. Of
the fourteen natural and synthetic Cdc42 inhibitors discussed, eight small molecule inhibitors
of Cdc42 have been used effectively in Ras-related cancer lines derived from breast,
colon, lung, and pancreatic cancer.
Conclusions: Cdc42 is a putative therapeutic target in Ras-related cancers since Cdc42
functions downstream of EGFR and Ras, Cdc42 promotes/activates EGFR and Ras signaling,
and Cdc42 inhibition in Ras-related cancers elicits anticancer effects.