|Location of mutation
||Switch II region of the G domain (Exon 3; Ensembl; Schubbert,
Shannon, and Bollag 2007)
|Frequency of NRAS mutations in
et al. 1994; COSMIC; Curtin et al.
't Veer et al. 1989)
|Frequency of Q61L 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 Q61L mutation results in an amino acid substitution at position 61 in
NRAS, from a glutamine (Q) to a leucine (L). 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.
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 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.
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
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.
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.
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.
k In a preclinical study, NRAS mutant melanoma cell line growth was
inhibited by the HSP90 inhibitor XL888 (Haarberg et al.