• What is NRAS?
  • NRAS in Colorectal Cancer
  • NRAS c.35G>A (G12D)
  • 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/colorectal-cancer/nras/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

NRAS in Colorectal Cancer

NRAS mutations occur in ~1–6% of colorectal cancers (COSMIC; De Roock et al. 2010; Irahara et al. 2009; Janku et al. 2007; Vaughn et al. 2011).

Wild type NRAS, together with wild type BRAF and KRAS, is associated response to EGFR antibody therapy (De Mattos-Arruda, Dienstmann, and Tabernero 2011; De Roock et al. 2010).

Several studies have shown that patients with NRAS-mutated tumors are less likely to respond to cetuximab or panitumumab, but this may not have an effect on PFS or overall survival (De Mattos-Arruda, Dienstmann, and Tabernero 2011; De Roock et al. 2010; Peeters et al. 2010).​

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2015. NRAS in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/nras/ (Updated June 18).

Last Updated: June 18, 2015

NRAS c.35G>A (G12D) Mutation in Colorectal Cancer

Location of mutation P-loop region of the G domain (Exon 2; Ensembl; Schubbert, Shannon, and Bollag 2007)
Frequency of NRAS mutations in colorectal cancer 1–6% of colorectal cancers (COSMIC; De Roock et al. 2010; Irahara et al. 2009; Janku et al. 2007; Vaughn et al. 2011)​​
Frequency of G12D mutations among NRAS-mutated colorectal cancers 16.1% (COSMIC)
Implications for Targeted Therapeutics
Response to EGFR monoclonal antibodies Confers reduced sensitivitya
Response to BRAF inhibitors Unknown at this time
Response to MEK inhibitors Unknown at this timeb

The G12D mutation results in an amino acid substitution at position 12 in NRAS, from a glycine (G) to an aspartic acid (D).

a Multiple studies have now shown that patients with tumors harboring mutations in KRAS or NRAS exons 2, 3, or 4 predict lack of response to anti-EGFR antibody therapy given in combination with chemotherapy (Ciardiello et al. 2014; Douillard et al. 2013; Karthaus et al. 2013; Peeters et al. 2014; Stintzing et al. 2014; Tejpar et al. 2014). While KRAS and NRAS testing is not required by the FDA, testing is recommended by NCCN (2014) and is required by EMEA (2014a; 2014b).

b Preclinical data have correlated the presence of activating mutations in NRAS with sensitivity to non-ATP competitive MEK inhibitors, AZD6244 and CI-1040 (Davies et al. 2007; Solit et al. 2006).


Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2017. NRAS c.35G>A (G12D) Mutation in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/nras/87/ (Updated February 20).

Last Updated: February 20, 2017

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