• What is NRAS?
  • NRAS in Lung Cancer
  • NRAS c.34G>A (G12S)
  • Clinical Trials

NRAS

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).

ras.png

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/lung-cancer/nras/?tab=0 (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. 2008; Ohashi 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. 2013).

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.).

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 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.34G>A (G12S) Mutation in Non-Small Cell Lung Cancer

Properties
Location of mutation P-loop region of the G domain (Exon 2; Ensembl; Schubbert, Shannon, and Bollag 2007)​
Frequency of NRAS mutations in NSCLC 1% (Brose et al. 2002; Ding et al. 2008)
Frequency of G12S mutations in NRAS-mutated NSCLC 3% (Ohashi et al. 2013)
Implications for Targeted Therapeutics
Response to EGFR TKIs Unknown at this timea
Response to anti-EGFR antibodies Unknown​ at this time
Response to MEK1/2 inhibitors Unknown​ at this timeb

The G12S mutation results in an amino acid substitution at position 12 in NRAS, from a glycine (G) to a serine (S).

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.

bNRAS mutations have been associated with sensitivity to MEK1/2 inhibitors in preclinical studies (Ohashi et al. 2013).

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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. 2017. NRAS c.34G>A (G12S) Mutation in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/nras/89/ (Updated February 20).

Last Updated: February 20, 2017

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