Small change, big effect: Taking RAS by the tail through suppression of post-prenylation carboxylmethylation

Abstract

Mutant RAS isoforms are the most common oncogenes affecting human cancers. After decades of effort in developing drugs targeting oncogenic RAS-driven cancers, we are still charting an unclear path. Despite recent developments exemplified by KRAS (G12C) inhibitors, direct targeting of mutant RAS remains a difficult endeavor. Inhibiting RAS function by targeting its post-translational prenylation processing has remained an important approach, especially with recent progress on the study of isoprenylcysteine carboxylmethyltransferase (ICMT), the unique enzyme for the last step of prenylation processing of RAS isoforms and other substrates. Inhibition of ICMT has shown efficacy both in vitro and in vivo in RAS-mutant cancer models. We will discuss the roles of RAS family of proteins in human cancers and the impact of post-prenylation carboxylmethylation on RAS driven tumorigenesis. In addition, we will review what is known of the molecular and cellular impact of ICMT inhibition on cancer cells that underlie its anti-proliferative and pro-apoptosis efficacy.

Therapeutic potential of RAS prenylation pharmacological inhibitors in the treatment of breast cancer, recent progress, and prospective

“…These molecules add farnesyl or geranylgeranyl to the cysteine residue of the CAAX-motif, respectively. 22,23 Attaching isoprenoid lipid to the protein increases hydrophobicity of the protein, facilitating their localization from the cytoplasm to the membranes. 19,24 Proteolysis step is mediated by RAS-converting CAAX endopeptidase 1, which cleaves off the last three amino acids (AAX) in the CAAX-motif.…”

“…Proteolysis step is mediated by RAS‐converting CAAX endopeptidase 1, which cleaves off the last three amino acids (AAX) in the CAAX‐motif. After disassociation of AAX, isoprenylcysteine appears at the C‐terminal, remaining for the next modifications . After proteolysis, the carboxy group of isoprenylcysteine is methylated by an enzyme called isoprenylcysteine carboxylmethyltransferase‐1 thereby neutralizing the negative charge of the C‐terminal, elevating its hydrophobicity and its affinity for the plasma membrane …”

“…The prenylation is remarkably affected by the regulation of these two enzymes, which can potentially recognize CAAX‐box. These molecules add farnesyl or geranylgeranyl to the cysteine residue of the CAAX‐motif, respectively . Attaching isoprenoid lipid to the protein increases hydrophobicity of the protein, facilitating their localization from the cytoplasm to the membranes .…”

Lipophilic Salirasib analogs with enhanced antiproliferative activity against human solid tumor cell lines

“…Guanine binding proteins (G proteins) such as Ras, Rap, Rho, and Rab enclose the largest group of isoprenylated proteins. Among these, Ras proteins have attracted particular attention because of the important role they play in carcinogenesis [2].…”

“…After prenylation, the protein can migrate to the endoplasmic reticulum, where a Ras Converting CAAX Endopeptidase 1 (RCE-1) cleaves the -AAX tail, leaving the C-terminus with an isoprenylcysteine. This motif is recognized by Isoprenylcysteine Carboxymethyl Transferase (ICMT), which catalyzes the transfer of a methyl group from an S-adenosyl-Lmethionine to the isoprenylated Ras terminus carboxylate to form an esther, allowing the membrane anchoring of Ras [2,5].…”