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Melanoma develops as a result of several genetic alterations, with UV radiation often acting as a mutagenic risk factor. Deep knowledge of the molecular signaling pathways of different types of melanoma allows better characterization and provides tools for the development of therapies based on the intervention of signals promoted by these cascades. The latest World Health Organization classification acknowledged the specific genetic drivers leading to melanoma and classifies melanocytic lesions into nine distinct categories according to the associate cumulative sun damage (CSD), which correlates with the molecular alterations of tumors. The largest groups are melanomas associated with low-CSD or superficial spreading melanomas, characterized by frequent presentation of the BRAFV600 mutation. High-CSD melanomas include lentigo maligna type and desmoplastic melanomas, which often have a high mutation burden and can harbor NRAS, BRAFnon-V600E, or NF1 mutations. Non-CSD-associated melanomas encompass acral and mucosal melanomas that usually do not show BRAF, NRAS, or NF1 mutations (triple wild-type), but in a subset may have KIT or SF3B1 mutations. To improve survival, these driver alterations can be treated with targeted therapy achieving significant antitumor activity. In recent years, relevant improvement in the prognosis and survival of patients with melanoma has been achieved, since the introduction of BRAF/MEK tyrosine kinase inhibitors and immune checkpoint inhibitors. In this review, we describe the current knowledge of molecular pathways and discuss current and potential therapeutic targets in melanoma, focusing on their clinical relevance of development.

The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

An emerging theme from large‐scale genetic screens that identify genes essential for cell fitness is that essentiality of a given gene is highly context‐specific. Identification of such contexts could be the key to defining gene function and also to develop novel therapeutic interventions. Here, we present Context‐specific Essentiality Network‐tools (CEN‐tools), a website and python package, in which users can interrogate the essentiality of a gene from large‐scale genome‐scale CRISPR screens in a number of biological contexts including tissue of origin, mutation profiles, expression levels and drug responses. We show that CEN‐tools is suitable for the systematic identification of genetic dependencies and for more targeted queries. The associations between genes and a given context are represented as dependency networks (CENs), and we demonstrate the utility of these networks in elucidating novel gene functions. In addition, we integrate the dependency networks with existing protein–protein interaction networks to reveal context‐dependent essential cellular pathways in cancer cells. Together, we demonstrate the applicability of CEN‐tools in aiding the current efforts to define the human cellular dependency map. Synopsis CEN‐tools allows users to navigate public large‐scale gene essentiality datasets and extract context‐specific essentiality networks, where context refers to the genetic background, gene expression, CNVs and other cell line features. Integrative analyses of the Project Score and DepMap datasets identify 190 novel core essential genes. Network visualisation of context‐specific gene co‐essentialities is achieved through Context‐specific Essentiality Networks (CENs). Integration of CENs with protein interaction networks prioritises potentially genetically interacting gene pairs. CEN‐tools discovers a link between SOX10 and SRF in metastatic melanoma cell lines and reveals cell processes essential in the context of NRAS‐mutant melanoma. Graphical Abstract CEN‐tools allows users to navigate public large‐scale gene essentiality datasets and extract context‐specific essentiality networks, where context refers to the genetic background, gene expression, CNVs and other cell line features.

Background Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. Methods Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAF V600 and NRAS Q61/G12/G13 mutations. Results After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07–0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. Conclusions Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.

mutations are common in melanoma and confer a worse prognosis. Although most patients with metastatic melanoma receive immune checkpoint inhibitors (ICIs), the impact of mutational status on their efficacy remains under debate. We performed a comprehensive literature search across several large databases. Inclusion criteria were trials, cohorts, and large case series that analyzed the primary outcome of objective response rate by mutational status in patients with melanoma treated with any line of ICI. At least two reviewers independently screened studies using Covidence software, extracted data, and assessed risk of bias. Standard meta-analysis was performed in R with sensitivity analysis and tests for bias. Data on 1770 patients from ten articles were pooled for meta-analysis, and the objective response rate to ICIs was calculated to compare -mutant and -wildtype melanoma. The objective response rate was 1.28 (95% confidence interval: 1.01-1.64). Sensitivity analysis identified the study by Dupuis et al. with influential impact on the pooled effect size and heterogeneity, favoring -mutant melanoma. In this meta-analysis evaluating the impact of mutational status on objective response to ICIs in metastatic melanoma, -mutant cutaneous melanoma demonstrated an increased likelihood of partial or complete tumor response, relative to -wildtype cutaneous melanoma. Genomic screening for mutations in patients with metastatic melanoma may improve predictive ability when initiating ICIs.

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS / RAF / MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS , KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

The oncogene of wild type neuroblastoma RAS viral oncogene homolog (NRAS) has been found to involve in the tumorigenesis of cancers. However, the role of NRAS in retinoblastoma (RB) progression remains largely unknown. The expression levels of NRAS, miR-183-5p and small nucleolar RNA host gene 16 (SNHG16) were measured using quantitative real-time polymerase chain reaction assay or Western blot assay, respectively. Cell proliferation and apoptosis were analyzed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or flow cytometry, respectively. Transwell assay was used to determine cell migration and invasion abilities. The interaction between miR-183-5p and NRAS or SNHG16 was analyzed using bioinformatics analysis and dual-luciferase reporter assay. NRAS was elevated in RB tissues and cell lines, knockdown of NRAS could inhibit proliferation, migration and invasion but induced apoptosis in vitro and suppressed tumor growth in vivo. NRAS was confirmed to be a target of miR-183-5p and was negatively regulated by miR-183-5p in RB cells. Moreover, overexpressed NRAS reversed miR-183-5p mediated inhibition on RB cell progression. Besides that, SNHG16 directly interacted with miR-183-5p and reduced miR-183-5p expression in RB cells. The suppression of RB cell progression induced by SNHG16 silencing could be partially attenuated by the inhibition of miR-183-5p. Besides that, SNHG16 could regulate NRAS expression through competitively binding to miR-183-5p in RB cells. NRAS functioned as an oncogene to contribute to RB progression by SNHG16/miR-183-5p/NRAS regulatory network, indicating a novel and promising therapeutic target for RB.

This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the “hot” codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594–596: 38; codons 597–602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients’ age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene.

Background: The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas. Methods: Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989–2020 in several clinical institutions were analyzed. NRAS, KIT, BRAF, IGF2R and SF3B1 mutational analyses by Sanger sequencing and next generation sequencing-based assay were performed in a subset of cases. Results: Of the triple (BRAF, NRAS, NF1)-negative cases, APC, KIT and KRAS are detected mainly in sinonasal, vulvovaginal and anorectal melanomas, respectively. NRAS, KIT, BRAF, IGF2R and SF3B1 mutations are detected in 19% (37/198), 22% (44/197), 12% (25/201), 16% (22/138) and 15% (20/133) of cases, respectively. In univariate analyses, advanced stage (p = 0.016), 65 years or older (p = 0.048) and presence of ulceration (p = 0.027) are significantly correlated with worse overall survival (OS), respectively. NRAS mutation significantly correlates with worse OS (p = 0.028) and worse melanoma-specific survival (MSS) (p = 0.03) for all cases of mucosal melanomas. In multivariate analyses, NRAS mutation remains as an independent predictor of worse OS (p = 0.036) and worse MSS (p = 0.024). Conclusion: NRAS mutation is a predictor of worse survival, independent of stage in mucosal melanomas. The significance of frequently mutated IGF2R in mucosal melanomas remains unclear.

Abstract Objectives Malignant acral melanoma (AM) is relatively infrequent in white patients. Molecular investigations have returned variable results regarding the mutational pattern. We sought to describe the mutation profile and clinicopathologic features of AM. Methods We investigated BRAF, KIT, and NRAS mutational status in a series of 31 AM samples from white patients. Results Nodular melanoma was the most common histopathologic subtype (48.4%), followed by acral lentiginous melanoma (25.8%) and superficial spreading melanoma (25.8%). BRAF, KIT, and NRAS mutational rates were 12.9%, 17.2%, and 30.0%, respectively. We observed significant associations between KIT mutational status and a thinner Breslow thickness compared with wild-type (WT) status (P = .002), NRAS mutation status and younger age compared with WT. In patients presenting at least one mutation, triple-WT patients presented metastases most frequently. Conclusions Although these data represent preliminary results, better knowledge of tumor biology and prognosis of AM can support the clinical approach and follow-up.