Abstract:

Oncogenic mutations are responsible for a majority of the malignancy of melanoma. Activating mutations of NRAS gene are found in 15%-20% melanoma cases, endowing the tumor cells with more aggressive phenotypes and greater difficulty to treat. The development of targeted inhibitor of mutant NRAS remains a big challenge since the mutation sites could hardly be druggable. Therefore, immune checkpoint inhibitors are currently recommended as the first-line therapy for NRAS mutant advanced melanoma albeit the response rate is still far from satisfaction. In recent years, the exploration of targeted therapy regimens has focused on the downstream pathway of NRAS, the mitogen-activated protein kinase (MAPK) pathway. A novel MEK1/2 inhibitor tunlametinib was reported to achieve an objective response rate (ORR) of 34.7% which is higher than the ORR of binimetinib in previous report. However, the phase Ⅰ trial of the pan-RAF inhibitor belvarafenib and the ERK inhibitor ulixertinib failed to show marked benefits. In the meanwhile, MEK inhibitor-based combination therapy has also achieved some progress: it was reported in the phase Ⅰb trial of the selective BRAF/CRAF inhibitor naporafenib (LXH254) combined with Trametinib in NRAS mutant melanoma that the ORR was 46.7%. The ORR of binetinib plus the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, ribociclib, was 32.5% in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. The response rate of the combination of focal adhesion kinase (FAK) inhibitor, IN10018, and cobimetinib was 38.5%. On the other hand, only 27.2% of patients carrying NRAS mutation responded partially to the combined regimen of immune checkpoint inhibitor programmed death ligand-1 (PD-L1) monoclonal antibody durvalumab+trametinib. In addition, some preclinical findings have also shown translational potentials: for example, heat shock protein 90 (HSP90) inhibitor XL888 and serine/threonine protein kinase 19 (STK19) inhibitors were found to inhibit the growth of NRAS mutant melanoma in animal models. This article reviewed the oncogenic roles of NRAS mutation in melanoma and the cutting-edge clinical trials for the treatment of NRAS mutant melanoma, aiming to provide alterative treatment options for clinical practice and inspire novel combination regimen.

Key words: NRAS mutation, Melanoma, Carcinogenesis, Targeted therapy