MEK inhibitors for the treatment of NRAS mutant melanoma

Abstract

Melanoma is increasing rapidly in incidence and prevalence, especially in younger females and older males. Treatment options have expanded beyond high-dose interleukin 2 and adoptive T-cell therapy to include inhibitors of immune checkpoints programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and small molecular inhibitors of pathways activated in melanoma, in particular the mitogen-activated protein kinase (MAPK) pathway. PD-1/CTLA-4 inhibitors and inhibitors of MAPK such as BRAF/MEK inhibitors have significantly improved survival in both the metastatic and, more recently, adjuvant settings. In this review, we discuss the preclinical data, clinical development, and potential use of novel MEK inhibitor binemetinib, particularly in the setting of NRAS mutant melanoma.

Targeting the ERK Signaling Pathway in Melanoma

“…RAS gene mutations were firstly associated with melanoma in 1984 [83]; this finding represented the first evidence of the association of an oncogene with this tumor. The most common NRAS mutation in melanoma (occurring in more than 80% of NRAS mutated samples), is a substitution of glutamine with arginine or lysine at position p.61 (NRAS Q61R/K/L ) as a result of the c.181C > A transversion (38%), of the c.182A > G transition (34%), or of the c.182A > T transversion (10%) in exon 3 of the gene, respectively [84,85]; other less frequent NRAS Q61 mutations are the NRAS Q61E/H/P as a result of the point mutations c.181C > G, c.183A > T, and c.182A > C, respectively [84,86] (genomic and protein mutations are designated following the recommendations in References [87,88]). Infrequent NRAS mutations can occur as substitutions at positions 12 and 13 of the protein as a result of point mutations in c.34, c.35, c.37, and c.38 positions of exon 2 of the gene (i.e., NRAS G12C/R/S/A/D/V and NRAS G13R/C/A/D/V as a result of c.34G > T/C/A, c.35G > C/A/T, c.37G > C/T, and c.38G > C/A/T, respectively) [84,86]; notably, the NRAS G12V mutation boosts wild-type BRAF ( WT BRAF) kinase activity 95-fold [89].…”

“…Besides overcoming paradoxical activation of monotherapy, another key therapeutic indication for MEK inhibitors is for the treatment of NRAS -mutant melanomas, which are more aggressive and have a poorer outcome than the BRAF -mutant counterparts [96]. In the former subset of tumors, the most promising target therapy to be tested in future clinical trials is a combination of MEK inhibitors (and, possibly, future ERK inhibitors), cell cycle inhibitors (in particular, CDK4/6 inhibitors), and agents inhibiting the PI3K-AKT-mTOR pathway (reviewed in References [85,195,196,197]).…”

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

“…As described above, they are used as either monotherapy or, more often, in combination with dabrafenib, vemurafenib, and encorafenib, respectively, in patients affected by BRAF-mutant advanced melanoma [ 15 , 35 , 36 ]. MEK inhibitors also determine modest benefits in terms of PFS for melanoma patients whose tumors carry missense mutations in NRAS (occurring in about 20% of melanoma cases) [ 37 , 38 , 39 , 40 , 41 ].…”

Current Molecular Markers of Melanoma and Treatment Targets

“…Positive expression of V600E in the nucleus as compared to the cytoplasm was correlated with worse tumor stage, lymph node metastasis, and depth of invasion [229]. Vemurafenib, dabrafenib, and encorafenib are FDA-approved drugs that have been developed as inhibitors of BRAF V600 mutations [38][39][40]. While monotherapy with BRAF inhibitors shows good efficacy against BRAF-mutant melanomas, patients can easily develop resistance through upregulation of RTKs or NRAS [230,231].…”