The role of wild type RAS isoforms in cancer

Abstract

Mutationally activated RAS proteins are critical oncogenic drivers in nearly 30% of all human cancers. As with mutant RAS, the role of wild type RAS proteins in oncogenesis, tumour maintenance and metastasis is context-dependent. Complexity is introduced by the existence of multiple RAS genes (HRAS, KRAS, NRAS) and protein "isoforms" (KRAS4A, KRAS4B), by the ever more complicated network of RAS signaling, and by the increasing identification of numerous genetic aberrations in cancers that do and do not harbour mutant RAS. Numerous mouse model carcinogenesis studies and examination of patient tumours reveal that, in RAS-mutant cancers, wild type RAS proteins are likely to serve as tumour suppressors when the mutant RAS is of the same isoform. This evidence is particularly robust in KRAS mutant cancers, which often display suppression or loss of wild type KRAS, but is not as strong for NRAS. In contrast, although not yet fully elucidated, the preponderance of evidence indicates that wild type RAS proteins play a tumour promoting role when the mutant RAS is of a different isoform. In non-RAS mutant cancers, wild type RAS is recognized as a mediator of oncogenic signaling due to chronic activation of upstream receptor tyrosine kinases that feed through RAS. Additionally, in the absence of mutant RAS, activation of wild type RAS may drive cancer upon the loss of negative RAS regulators such as NF1 GAP or SPRY proteins. Here we explore the current state of knowledge with respect to the roles of wild type RAS proteins in human cancers.

Keywords: Cancer; Isoform; Mutant; RAS; RASGAP; Wild type.

Figure 1. RAS isoforms

A. Sequence identity and divergence between the four human RAS proteins include conformational changes to the switch I (SI; amino acids 30–38) and II (SII; 59–76) regions in the GDP and GTP bound states, hence regulating effector binding affinity. G domain, GTP-binding. HVR, hypervariable region. CAAX, Cysteine, Aliphatic, Aliphatic, Any amino acid. Sites of posttranslational modifications are indicated by underlines and boxes; P, phosphorylation. B. Frequency of missense mutations in the three human RAS genes and at the three hotspots for RAS mutations (codons G12, G13 and Q61).

Figure 2. Interplay between wild type and mutant RAS alleles in cancer

(A) Wild type RAS proteins can display either tumour promoting or tumour suppressing functions, depending on context. Some ways in which mutant KRAS promotes tumourigenesis are by (B) allosteric activation of the RAS GEF SOS1 to activate wild type HRAS and NRAS, or (C) activation of eNOS (endothelial nitric oxide synthase) to nitrosylate and activate wild type HRAS. Additionally (D), wild type HRAS and NRAS can block inhibition of the G2 DNA damage checkpoint to promote genome maintenance.

Figure 3. Mutational activation of the RAS signaling network in cancer

RAS function can be activated directly by mutation of RAS or indirectly by mutational activation or loss of components upstream or downstream of RAS. Missense mutation frequencies are indicated in parentheses and were compiled from COSMIC.