Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Abstract

RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development.

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

“…FTase has been recently suggested as a drug target in the development of anti-cancer therapy (7,9). In the present study, it was demonstrated that FTI-277 exerted a more potent anti-proliferative effect on breast cells expressing an active mutant of H-Ras (H-Ras-MCF10A and Hs578T cells) than breast cells expressing wild-type H-Ras (MDA-MB-231 cells).…”

“…Farnesylation by FTase is the first irreversible, rate-limiting step for Ras membrane association and an obligate modification for oncogenic Ras biological activity (7). Initial attempts to inhibit FTase have been made in the development of anti-cancer agents (2,8,9).…”

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

“…The Kras gene encodes the protein of p21 RAS, which is a small GTPase that acts as a molecular switch by coupling cell membrane growth signals to intracellular signaling pathways and transcription factors to control multiple cellular processes (25,26). Oncogenically mutated RAS proteins fail to cycle "off" from the active, GTP-bound state to the inactive GDP-bound state, and thereby accumulated in the constitutive "on" configuration (27). Kras is the most common oncogene that has been found to be mutated in pancreatic cancer.…”

Genetics and biology of pancreatic ductal adenocarcinoma

“…In the case of KRAS, this attachment requires the post-translational lipid modification of farnesylation (Cox et al 2015). While early efforts to target KRAS farnesylation have failed therapeutically, new small molecule inhibitors have been developed that instead target PDEδ, which binds to farnesylated KRAS and enhances its localization to plasma membranes (Chandra et al 2012;Zimmermann et al 2013).…”