Healthy Happy Blog

by Richard Smith

Cutaneous Melanomas Have Mutations In Nras Gtpases

It is estimated that one third of all human cancers have oncogenic mutations in the RAS family of small GTPases. These annotations have led to preclinical studies of RAS-induced tumor genesis that have shown that inactivation of RAS after the establishment of tumors leads to fast cell death and tumor regression.2,3 Following these studies, therapeutic strategies to inactivate RAS-dependent signaling in cancer cells have been of major interest but, unfortunately, also a significant challenge. Owing to recent advances in therapeutic strategies for difficult targets like RAS, the field is poised to evaluate a number of approaches to target NRAS in melanoma during the next 5 years.

The RAS family of GT Passes consists of KRAS, HRAS and NRAS. Although mutations in KRAS are the most frequent RAS mutations in human malignant disease,4 in melanoma, the most commonly mutated isoform is NRAS, with 15% of cases harboring point mutations.5-7 The most common mutations occur at codons 12, 61, or, less frequently, 13, leading to defective GTPase activity, accumulation of RAS-GTP,8 and insensitivity to the normal regulation of RAS signaling by guanine nucleotide exchange factors (GEFs; Sos1/2, RASGRP1-4, and RASGRF1/2 proteins) and GTPase-activating proteins (GAPs; NF1 and p120GAP).9 Downstream RAS effecter molecules include class I phosphatidylinositol 3-OH kinase (PI3K), RAF kinases, RALGEFs, the RAC exchange factor TIAM1, and phospholipase C[Latin Small Letter Open E].

9 Genetic evidence in experimental systems provides strong evidence that the RAF/MEK/ERK pathway is critical to the ability of RAS to induce cell proliferation, migration, and survival.10 Similar studies have also shown that RAS-dependent transformation requires activation of cyclin D111-13 and down-regulation of the CDK inhibitor p27KIP1,13 implicating RAS proteins in integrating mitogenic signaling with cell cycle progression. In experimental studies, RAS is required to activate CDK2 and CDK4 and inactivate pRB that is also required for cell cycle progression.10 The importance of these downstream cell cycle processes in RAS-dependent transformation of melanocytes is highlighted by cooperation between loss of the tumor suppressor and negative regulator of the cell cycle, CDKN2A, with mutant RAS in inducing melanomas in genetically modified mice.

14,15 Human genetic studies examining germline mutations in components in the RAS signaling pathway have been identified in the autosomal dominant disorder Noonan syndrome.16,17 Overall defects in 4 genes all involving the RAS/RAF/MEK/ERK pathway (PTPN11, RAF1, SOS1, and KRAS) can cause this disorder that is characterized by an increased incidence of certain malignancies, further highlighting the functional and biochemical relationship between RAS and this pathway in cancer.18 There is a high frequency of activating mutations in proteins of the RAS/RAF/MEK/ERK pathway in melanoma. The serine threonine kinase BRAF is mutated at V600 in approximately 50% of cases of melanoma. In contrast, the NRAS gene is mutated in 15% to 20% of melanomas.

19-21 Notably, both BRAF and NRAS mutations also occur in benign nevi,22 implicating other genetic events in the transition to malignancy. Mutations in BRAF and NRAS are almost invariably mutually exclusive, suggesting that they may function on the same pathway.19-21 interestingly; studies on cell lines have shown that PTEN loss, another common genetic aberration in melanoma, is relatively uncommon in melanomas harboring NRAS mutations, suggesting that NRAS and PTEN may also function on a shared pathway.

05 Oct 2017 author: Richard Smith