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
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. NRAS. My Cancer
(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.).
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.183A>C (Q61H) Mutation in Melanoma
|Location of mutation
||Switch II region of the G domain (Exon 3; Ensembl; Schubbert, Shannon, and Bollag
|Frequency of NRAS mutations in
et al. 1994; COSMIC; Curtin et al.
2005; van 't
Veer et al. 1989)
|Frequency of Q61H mutation among
NRAS-mutated malignant melanomas
|Implications for Targeted Therapeutics
|Response to BRAF inhibitors
||Unknown at this timea
|Response to MEK inhibitors
|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 Q61H mutation results in an amino acid substitution at position 61 in NRAS,
from a glutamine (Q) to a histidine (H). 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.
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.
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
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
f Clinical trials are underway evaluating the effects of binimetinib in
combination with BYL719, dactolisib, or BKM120 (Johnson, Smalley, and
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
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.
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).
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2017. NRAS c.183A>C (Q61H)
Mutation in Melanoma. My Cancer
(Updated April 6).
Last Updated: April 6, 2017
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