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. 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 review see (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.
Last Updated: June 1, 2012
NRAS Mutations 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).
Last Updated: June 1, 2012
NRAS c.35G>A (G12D) Mutation in Colorectal Cancer
| Properties | |
|---|---|
| Location of mutation | Codon 12 |
| 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 mutant colorectal cancers | ~17% (COSMIC) |
| Implications for Targeted Therapeutics | |
| Response to EGFR monoclonal antibodies | Unknown at this timea |
| 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).
The role of NRAS mutations for selecting/prioritizing anti-cancer treatment, including cytotoxic chemotherapy and targeted agents, is unknown at this time.
a 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).
b Pre-clinical data has 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).
Last Updated: July 19, 2012
NRAS-Associated Colorectal Cancer Clinical Trials
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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