NRAS, short for Neuroblastoma RAS, is an oncogene belonging to the RAS family of guanosine 5'-triphosphate (GTP)-binding proteins. It plays a crucial role in linking cell surface receptor activation to various cellular processes such as proliferation, apoptosis, and differentiation, mainly through the MAPK/ERK signaling pathway [7]. Genetic alterations in NRAS are commonly found in human cancers, highlighting its significance in tumorigenesis. Mouse models, including gene knockout (KO) or conditional knockout (CKO) models, can be valuable for studying NRAS function in vivo.

NRAS mutations account for 15-30% of melanoma cases [1,2,6,7]. NRAS-driven melanomas are challenging to treat due to lack of efficient targeted therapies and high aggressiveness [1]. Understanding how these melanomas develop therapy resistance is crucial for better treatment. For example, a serine/threonine kinase STK19 was identified as a novel NRAS activator, phosphorylating NRAS to promote melanocyte malignant transformation [2]. In myeloid leukemia, RAB27B controls NRAS palmitoylation and trafficking to the plasma membrane for activation, and its depletion inhibits growth of NRAS-mutant cell lines [3]. In glioblastoma, circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance via the NRAS/MEK1/ERK1-2 signaling pathway [4]. In human endothelial cells, the NRASQ61R mutation causes vascular malformations and abnormal angiogenesis, and the MAP kinase inhibitor U0126 can prevent related morphological changes [5].

In conclusion, NRAS is a key regulator in multiple cellular processes and is significantly involved in diseases like melanoma, myeloid leukemia, glioblastoma, and vascular malformations. Mouse models, if available in the future, could potentially provide deeper insights into the role of NRAS in these disease conditions, contributing to the development of more effective therapeutic strategies.

References:

1. Randic, Tijana, Kozar, Ines, Margue, Christiane, Utikal, Jochen, Kreis, Stephanie. 2021. NRAS mutant melanoma: Towards better therapies. In Cancer treatment reviews, 99, 102238. doi:10.1016/j.ctrv.2021.102238. https://pubmed.ncbi.nlm.nih.gov/34098219/

2. Yin, Chengqian, Zhu, Bo, Zhang, Ting, Deng, Xianming, Cui, Rutao. 2019. Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis. In Cell, 176, 1113-1127.e16. doi:10.1016/j.cell.2019.01.002. https://pubmed.ncbi.nlm.nih.gov/30712867/

3. Ren, Jian-Gang, Xing, Bowen, Lv, Kaosheng, Philips, Mark R, Tong, Wei. 2023. RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia. In The Journal of clinical investigation, 133, . doi:10.1172/JCI165510. https://pubmed.ncbi.nlm.nih.gov/37317963/

4. Wei, Yutian, Lu, Chenfei, Zhou, Peng, Shi, ZhuMei, You, Yongping. . EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1-2 signaling. In Neuro-oncology, 23, 611-624. doi:10.1093/neuonc/noaa214. https://pubmed.ncbi.nlm.nih.gov/32926734/

5. Boscolo, Elisa, Pastura, Patricia, Schrenk, Sandra, Malik, Punam, Le Cras, Timothy D. 2022. NRASQ61R mutation in human endothelial cells causes vascular malformations. In Angiogenesis, 25, 331-342. doi:10.1007/s10456-022-09836-7. https://pubmed.ncbi.nlm.nih.gov/35391614/

6. Queirolo, Paola, Spagnolo, Francesco. 2017. Binimetinib for the treatment of NRAS-mutant melanoma. In Expert review of anticancer therapy, 17, 985-990. doi:10.1080/14737140.2017.1374177. https://pubmed.ncbi.nlm.nih.gov/28851243/

7. Mandalà, Mario, Merelli, Barbara, Massi, Daniela. 2014. Nras in melanoma: targeting the undruggable target. In Critical reviews in oncology/hematology, 92, 107-22. doi:10.1016/j.critrevonc.2014.05.005. https://pubmed.ncbi.nlm.nih.gov/24985059/