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 Non-Small Cell Lung Cancer (NSCLC)
Somatic mutations in NRAS have
been found in ~1% of all NSCLC (Brose et al. 2002; Ding et al.
et al. 2013). NRAS mutations are more commonly found in lung cancers with
adenocarcinoma histology and in those with a history of smoking (Ohashi et al.
2013). In the majority of cases, these mutations are missense mutations that
introduce an amino acid substitution at position 61. Mutations at position 12 have also been
described (Ohashi et
al. 2013). The result of these mutations is constitutive activation of NRAS
signaling pathways. Currently, there are no direct anti-NRAS therapies available, but
preclinical models suggest that MEK inhibitors may be effective (Ohashi et al.
In the vast majority of cases, NRAS mutations
are non-overlapping with other oncogenic mutations
found in NSCLC (e.g., EGFR mutations, ALK rearrangements, etc.).
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. NRAS in Non-Small Cell
Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/nras/
(Updated June 18).
Last Updated: June 18, 2015
NRAS c.182A>T (Q61L) Mutation in Non-Small Cell Lung Cancer
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 or prioritizing anti-cancer treatment, including cytotoxic chemotherapy and
targeted agents, is unknown at this time.
aKRAS mutations, which
are more common in lung cancer than NRAS mutations, have been associated with
decreased sensitivity to EGFR TKIs.
b In preclinical studies, cell lines harboring the Q61L mutation were sensitive to the MEK1/2
inhibitors selumetinib and trametinib (Ohashi et al. 2013).
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2017. NRAS c.182A>T (Q61L)
Mutation in Non-Small Cell Lung Cancer. My
Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/nras/76/
(Updated February 20).
Last Updated: February 20, 2017
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