NRAS

aka N-ras, NRAS proto-oncogene, GTPase

NRAS is one of the three RAS switch proteins that pass growth signals into the cell. When a mutation jams it on, as in a share of melanomas, the cell keeps dividing; today's drugs reach it indirectly through MEK or RAF, and pan-RAS inhibitors that bind the active form are in trials.

NRAS (chromosome 1p13.2) encodes a small GTPase of the RAS-MAPK pathway that binds GDP and GTP, hydrolyses GTP and relays signals for proliferation and survival; its turnover is controlled by LZTR1-directed ubiquitination through a CUL3 ligase complex (UniProt P01111). In OnCo, NRAS appears as the mutation that defines the melanoma population for the MEK inhibitor tunlametinib (approved in China in 2024 for NRAS-mutant melanoma, a group with no targeted therapy elsewhere) and for the pan-RAF inhibitor naporafenib studied with trametinib; as a resistance marker, with KRAS, that excludes patients from cetuximab in colorectal cancer and that the Tempus xT CDx companion diagnostic reports; and as one of the three isoforms the pan-RAS(ON) inhibitor JYP0015 binds, covering mutations at codons 12, 13, 61, 117 and 146.

NRAS: what it is and how drugs act on it · animated schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · NRAS is one of the three RAS switch proteins that pass growth signals into the cell. When a mutation jams it on, as in a share of melanomas, the cell keeps dividing; today's drugs reach it indirectly through MEK or RAF, and pan-RAS inhibitors that bind the active form are in trials.

1 · What it is
NRAS is one of the three RAS switch proteins that pass growth signals into the cell. When a mutation jams it on, as in a share of melanomas, the cell keeps dividing; today's drugs reach it indirectly through MEK or RAF, and pan-RAS inhibitors that bind the active form are in trials.
2 · What goes wrong in cancer
RAS proteins share the GDP/GTP cycle and intrinsic GTPase activity; neurofibromin (NF1) stimulates that hydrolysis and so switches RAS off (UniProt P21359).
3 · How drugs use it
1 product aims at NRAS: small molecules. Drugs fit a pocket that exists only in one shape of the mutant protein and hold it there, off.

Full dossier: hotspots, trials, resistance, assays, models, open questions →

External identifiers

NRASHGNCEnsemblUniProtAlphaFold DBOpen TargetsCIViCOncoKBCOSMICcBioPortalDepMapHuman Protein AtlasNCBI GeneOMIM

Biology

RAS proteins share the GDP/GTP cycle and intrinsic GTPase activity; neurofibromin (NF1) stimulates that hydrolysis and so switches RAS off (UniProt P21359). Mutant NRAS stays GTP-bound, so the corpus drugs act below it (tunlametinib on MEK, naporafenib on RAF) or on the active state of all RAS isoforms (JYP0015). The lenzilumab record notes that chronic myelomonocytic leukaemia progenitors with NRAS, KRAS or CBL mutations proliferate in response to very low GM-CSF levels.

Where it is found

Melanoma with NRAS mutation (tunlametinib, naporafenib)
Colorectal cancer (RAS testing of KRAS and NRAS exons 2 to 4 before cetuximab; mutant tumours excluded)
Chronic myelomonocytic leukaemia progenitors (lenzilumab rationale)

Class

oncogene · NRAS

Identifiers

HGNC HGNC:7989Ensembl ENSG00000213281UniProt P01111NCBI Gene 4893

Products

1top

Phase 2small molecule (structure undisclosed or not yet in PubChem)

JYP0015

JYP0015 is an experimental small-molecule drug from Guangzhou JOYO Pharma in phase 2 trials for pancreatic ductal adenocarcinoma, non-small-cell lung cancer and colorectal cancer, aimed at KRAS.