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Review
. 2014 Aug 15;20(16):4186-92.
doi: 10.1158/1078-0432.CCR-13-3270. Epub 2014 Jun 3.

Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia

Douglas B Johnson  1 , Keiran S M Smalley  2 , Jeffrey A Sosman  3
Affiliations
Review

Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia

Douglas B Johnson et al. Clin Cancer Res. .

Abstract

Successful targeting of specific oncogenic "driver" mutations with small-molecule inhibitors has represented a major advance in cancer therapeutics over the past 10 to 15 years. The most common activating oncogene in human malignancy, RAS (rat sarcoma), has proved to be an elusive target. Activating mutations in RAS induce mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-AKT pathway signaling and drive malignant progression in up to 30% of cancers. Oncogenic NRAS mutations occur in several cancer types, notably melanoma, acute myelogenous leukemia (AML), and less commonly, colon adenocarcinoma, thyroid carcinoma, and other hematologic malignancies. Although NRAS-mutant tumors have been recalcitrant to targeted therapeutic strategies historically, newer agents targeting MAP/ERK kinase 1 (MEK1)/2 have recently shown signs of clinical efficacy as monotherapy. Combination strategies of MEK inhibitors with other targeted agents have strong preclinical support and are being evaluated in clinical trials. This review discusses the recent preclinical and clinical studies about the role of NRAS in cancer, with a focus on melanoma and AML.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

J.A. Sosman is a consultant/advisory board member for Bristol-Myers Squibb and Genentech.

Figures

Figure 1
Figure 1
Wild-type RAS activation in normal cells. The RAS activation process is triggered by interaction between a receptor tyrosine kinase and its ligand. This recruits an adaptor molecule (growth factor receptor-bound protein 2 [GRB2] and others) that subsequently causes activation of son of sevenless homolog (SOS) and other guanine nucleotide exchange factors (GEFs). GEFs catalyze the conversion of RAS-GDP (inactive) to RAS-GTP. GTPase-activating proteins (GAPs, including neurofibromin 1 [NF1]) oppose this activation step. Activated RAS then signals through the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)–AKT, and Ral–guanine nucleotide dissociation stimulator (GDS) pathways to induce cell growth and proliferation. SHC, Src homology 2 domain-containing transforming protein.
Figure 2
Figure 2
Therapeutic strategies to target mutant NRAS: Direct targeting strategies include inhibition of RAS transcription by RNA interference and blockade of posttranslational modification by farnesyltransferase inhibitors. Agents that block downstream mitogen-activated protein kinase (MAPK) signaling include inhibitors of MAPK/ERK kinase (MEK) and extracellular signal–regulated kinase (ERK) as well as paradox-breaker RAF inhibitors. Agents targeting cell cycle regulation and the phosphoinositide 3-kinase (PI3K)–AKT pathway are also being evaluated in combination with MAPK pathway inhibitors. CDK, cyclin-dependent kinase; mTOR, mammalian target of rapamycin; Rb, retinoblastoma.
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