• What is NRAS?
  • NRAS in Melanoma
  • NRAS c.34G>T (G12C)
  • Clinical Trials


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; the degree of redundancy remains a topic of investigation (reviewed in Pylayeva-Gupta et al. 2011). 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 reviews see Karnoub and Weinberg 2008 and 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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. NRAS. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/nras/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

NRAS in Melanoma

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.).

Contributors: Christine M. Lovly, M.D., Ph.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.

Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. NRAS in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/nras/ (Updated June 18).

Last Updated: June 18, 2015

NRAS c.34G>T (G12C) Mutation in Melanoma

Location of mutation P-loop region of the G domain (Exon 2; Ensembl; Schubbert, Shannon, and Bollag 2007)
Frequency of NRAS mutations in malignant melanomas 13–25% (Ball et al. 1994; COSMIC; Curtin et al. 2005; van 't Veer et al. 1989)
Frequency of G12C mutation among NRAS-mutated malignant melanomas <1% (COSMIC)
Implications for Targeted Therapeutics
Response to BRAF inhibitors Unknown at this timea
Response to MEK inhibitors Unknown at this timeb
Response to amuvatinib Unknown at this timec
Response to ERK inhibitors Unknown at this timed
Response to combination MEK/AKT inhibitors Unknown at this timee
Response to combination MEK/PI3K inhibitors Unknown at this timef
Response to combination MEK/CDK4/6 inhibitors Unknown at this timeg
Response to sorafenib/tivantinib combination Confers increased sensitivityh
Response to combination WNT3A and MEK inhibition Unknown at this timei
Response to AKT/NF-kappaB inhibitors Unknown at this timej
Response to HSP90 inhibitors Unknown at this timek


The G12C mutation results in an amino acid substitution at position 12 in NRAS, from a glycine (G) to a cysteine (C). The role of NRAS mutations for selecting/prioritizing anticancer 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 have 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 binimetinib (MEK162), 20% of patients with NRAS Q61- mutated tumors showed partial responses (Ascierto et al. 2013). In a phase I clinical trial of selumetinib (AZD6244), two melanoma patients with NRAS Q61-mutated tumors had stable disease while one had a partial response (Adjei et al. 2008). In a preclinical study, melanoma cell lines with both BRAF V600E mutations and NRAS Q61K mutations were resistant to BRAF inhibitor vemurafenib but sensitive to MEK inhibitor selumetinib (Atefi et al. 2011).

c In a preclinical study, NRAS mutant melanoma cell line growth was inhibited by amuvatinib, a KIT, MET, PDGFRA, and RAD51 inhibitor (Fedorenko et al. 2014).

d In a preclinical study, the ERK1/2 inhibitor PB04 (PLX7904) inhibited growth of a melanoma cell line harboring both BRAF V600E and NRAS Q61K; this cell line was also vemurafenib-resistant (Johnson, Smalley, and Sosman 2014; Le et al. 2013). In another preclinical study, BRAF mutant, KRAS mutant, and NRAS mutant xenograft models were sensitive to the ERK1/2 inhibitor SCH772984 (Morris et al. 2013).

e A clinical trial is underway evaluating the effects of combination trametinib- uprosertib in BRAF wild type and either NRAS wild type or NRAS mutant melanomas (Johnson, Smalley, and Sosman 2014).

f Clinical trials are underway evaluating the effects of binimetinib in combination with BYL719, dactolisib, or BKM120 (Johnson, Smalley, and Sosman 2014).

g In a phase Ib trial, preliminary efficacy was demonstrated in patients with NRAS- mutated melanoma when treated with combination of binimetinib and the CDK4/6 inhibitor ribociclib (LEE011); the phase II portion is ongoing (Sosman et al. 2014). Clinical trials are underway evaluating the effects of combination trametinib and palbociclib (Johnson, Smalley, and Sosman 2014).

h A phase I trial of sorafenib in combination with tivantinib showed preliminary activity in NRAS-mutated melanoma (Puzanov et al. 2015).

i In a preclinical study, NRAS mutant melanoma cell lines treated with WNT3A (a protein that activates the Wnt signaling pathway) and the MEK inhibitor selumetinib were susceptible to apoptosis (Conrad et al. 2012).

j In a preclinical study, NRAS mutant melanoma cell line growth was inhibited by the AKT/NF-kappaB small molecule inhibitor BI-69A11 (Feng et al. 2012).

k In a preclinical study, NRAS mutant melanoma cell line growth was inhibited by the HSP90 inhibitor XL888 (Haarberg et al. 2013).

Contributors: Christine M. Lovly, M.D., Ph.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.

Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2017. NRAS c.34G>T (G12C) Mutation in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/nras/86/ (Updated February 20).

Last Updated: February 20, 2017

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