Three different human RAS genes have been identified: KRAS (homologous to the oncogene from the Kirsten rat sarcoma virus), HRAS (homologous to the oncogene from the Harvey rat sarcoma virus), and NRAS (first isolated from a human Neuroblastoma). The different RAS genes are highly homologous but functionally distinct. RAS proteins are small GTPases which cycle between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound forms. RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. RAS can activate several downstream effectors, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).
RAS has been implicated in the pathogenesis of several cancers. Activating mutations within the RAS gene result in constitutive activation of the RAS GTPase, even in the absence of growth factor signaling. The result is a sustained proliferation signal within the cell.
Specific RAS genes are recurrently mutated in different malignancies. NRAS mutations are particularly common in melanoma, hepatocellular carcinoma, myeloid leukemias, and thyroid carcinoma [for review see (Schubbert, Shannon, and Bollag 2007)].
Figure 1. Simplified schematic of RAS signaling pathways. Growth factor binding to receptor tyrosine kinases results in RAS activation. The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: June 1, 2012
Somatic mutations in NRAS have been found in ~13–25% of all malignant melanomas (Ball et al. 1994; Curtin et al. 2005; van 't Veer et al. 1989). In the majority of cases, these mutations are missense mutations which introduce an amino acid substitution at positions 12, 13, or 61. The result of these mutations is constitutive activation of NRAS signaling pathways. NRAS mutations are found in all melanoma subtypes, but may be slightly more common in melanomas derived from chronic sun-damaged (CSD) skin (Ball et al. 1994; van 't Veer et al. 1989). Currently, there are no direct anti-NRAS therapies available.
In the vast majority of cases, NRAS mutations are non-overlapping with other oncogenic mutations found in melanoma (e.g., BRAF mutations, KIT mutations, etc.).
Last Updated: October 8, 2012
|Location of mutation||Codon 13|
|Frequency of NRAS mutations in malignant melanomas||~13–25% (Ball et al. 1994; Curtin et al. 2005; van 't Veer et al. 1989)|
|Frequency of G13V mutation among NRAS mutant malignant melanomas||2% (COSMIC)|
|Implications for Targeted Therapeutics|
|Response to BRAF inhibitors||Unknown at this timea|
|Response to MEK inhibitors||Unknown at this timeb|
|Response to KIT inhibitors||Unknown at this time|
The G13V mutation results in an amino acid substitution at position 13 in NRAS, from a glycine (G) to a valine (V).
The role of NRAS mutations for selecting/prioritizing anti-cancer treatment, including cytotoxic chemotherapy and targeted agents, is unknown at this time.
a Clinical data for RAS-mutated melanomas treated with BRAF inhibitors is lacking. However, preclinical data has demonstrated a paradoxical stimulation of the MAPK signaling pathway and thus enhanced tumor growth in melanoma cells harboring mutant RAS (Hatzivassiliou et al. 2010; Poulikakos et al. 2010).
b In a phase II clinical trial of MEK162, 20% of patients with NRAS Q61-mutated tumors showed partial responses (Ascierto et al. 2013). In a phase I clinical trial of AZD6244, two melanoma patients with NRAS Q61-mutated tumors had stable disease while one had a partial response (Adjei et al. 2008).
Last Updated: April 15, 2013
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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