The therapeutically actionable long non-coding RNA 'T-RECS' is essential to cancer cells' survival in NRAS/MAPK-driven melanoma.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.

Deconstructing the role of MALAT1 in MAPK-signaling in melanoma: insights from antisense oligonucleotide treatment.

The long non-coding RNA (lncRNA) MALAT1 is a regulator of oncogenesis and cancer progression. MAPK-pathway upregulation is the main event in the development and progression of human cancer, including melanoma and recent studies have shown that MALAT1 has a significant impact on the regulation of gene and protein expression in the MAPK pathway. However, the role of MALAT1 in regulation of gene and protein expression of the MAPK-pathway kinases RAS, RAF, MEK and ERK in melanoma is largely unknown.

Clinical melanoma characteristics and survival-a single-center retrospective study between 2000 and 2010.

The aim of this study was to characterize clinical, histological, and outcome features of primary melanoma in 1329 patients managed at a single-center institution between 2000 and 2010. Parameters included age at diagnosis, sex, tumor location, histology, stage, Breslow thickness, and sentinel lymph node status among others. The mean age at diagnosis was 59.

MEK/CDK4,6 co-targeting is effective in a subset of NRAS, BRAF and 'wild type' melanomas.

Targeted therapy has become a cornerstone for the treatment of melanoma patients. Targeting NRAS function is particularly challenging. To date, only single MEK inhibitor treatment was able to show minimal clinical efficacy.

The lincRNA MIRAT binds to IQGAP1 and modulates the MAPK pathway in NRAS mutant melanoma.

Despite major advances in targeted melanoma therapies, drug resistance limits their efficacy. Long noncoding RNAs (lncRNAs) are transcriptome elements that do not encode proteins but are important regulatory molecules. LncRNAs have been implicated in cancer development and response to different therapeutics and are thus potential treatment targets; however, the majority of their functions and molecular interactions remain unexplored.

Treatment of metastatic melanoma: a multidisciplinary approach.

The prognosis of stage IV metastatic melanoma is poor. An overall 1-year survival of 25.5% and a median survival of 6.

New insights in melanoma biomarkers: long-noncoding RNAs.

Melanoma is one of the leading cancers worldwide, distinguished for its malignancy and low survival rates. Although the poor outcome could improve with an early diagnosis and a good monitoring of the disease, current melanoma biomarkers display several limitations which make them useless. Interestingly, long-noncoding RNAs are secreted into the bloodstream inside exosomes by a wide range of malignant cells, and several of them have been validated as promising circulating molecular signatures of other tumors, but not melanoma.

Pharmacological inhibitors of c-KIT block mutant c-KIT mediated migration of melanocytes and melanoma cells in vitro and in vivo.

Mutations in the receptor tyrosine kinase c-KIT (KIT) are frequent oncogenic alterations in melanoma and are predominantly detected in tumors of acral, mucosal, and chronically sun-damaged skin. Research indicates that melanocytes with aberrant KIT signaling can be found in the distant periphery of the primary tumor; However, it is hitherto unknown whether KIT might confer a migratory advantage, thereby enabling genetically abnormal cells to populate a distal area. In this study, we investigated the role of mutant KIT in melanocyte- and melanoma cell migration using KIT mutant lines as well as genetically manipulated murine and primary human melanocytes.

Phosphoproteomic Analyses of NRAS(G12) and NRAS(Q61) Mutant Melanocytes Reveal Increased CK2α Kinase Levels in NRAS(Q61) Mutant Cells.

In melanoma, mutant and thereby constantly active neuroblastoma rat sarcoma (NRAS) affects 15-20% of tumors, contributing to tumor initiation, growth, invasion, and metastasis. Recent therapeutic approaches aim to mimic RAS extinction by interfering with critical signaling pathways downstream of the mutant protein. This study investigates the phosphoproteome of primary human melanocytes bearing mutations in the two hot spots of NRAS, NRAS(G12) and NRAS(Q61).

Oncogenic KIT mutations in different exons lead to specific changes in melanocyte phospho-proteome.

Unlabelled: Mutations in the proto-oncogene c-KIT (KIT) are found in several cancers, and the site of these mutations differs markedly between cancer types. We used site directed mutagenesis to induce KIT(559), KIT(642) and KIT(816) mutations in primary human melanocytes (PHM) and we investigated the impact of each mutation on KIT function. We studied canonical KIT-signaling pathways by immunoblotting, and we used stable isotope labeling by amino acids in cell culture (SILAC) and kinase prediction models to identify kinases differently activated in respective mutants.

Searching for the Chokehold of NRAS Mutant Melanoma.

Up to 18% of melanomas harbor mutations in the neuroblastoma rat-sarcoma homolog (NRAS). Yet, decades of research aimed to interfere with oncogenic RAS signaling have been largely disappointing and have not resulted in meaningful clinical outputs. Recent advances in disease modeling, structural biology, and an improved understanding of RAS cycling as well as RAS signaling networks have renewed hope for developing strategies to selectively block hyperactive RAS function.

Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells.

Oncogenic NRAS mutations are frequent in melanoma and lead to increased downstream signaling and uncontrolled cell proliferation. Since the direct inhibition of NRAS is not possible yet, modulators of NRAS posttranslational modifications have become an area of interest. Specifically, interfering with NRAS posttranslational palmitoylation/depalmitoylation cycle could disturb proper NRAS localization, and therefore decrease cell proliferation and downstream signaling.

Melanoma risk perception and prevention behavior among African-Americans: the minority melanoma paradox.

Introduction: Melanoma is the most deadly type of skin cancer with 75% of all skin cancer deaths within the US attributed to it. Risk factors for melanoma include ultraviolet exposure, genetic predisposition, and phenotypic characteristics (eg, fair skin and blond hair). Whites have a 27-fold higher incidence of melanoma than African-Americans (AA), but the 5-year survival is 17.

Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression.

Importance: Immunomodulatory anticancer drugs, such as the anti-programmed death-1 drug pembrolizumab, have shown promising results in trials, and more patients will receive such treatments. Little is known about cutaneous adverse events (AEs) caused by these drugs and their possible correlation with treatment response.

Objective: To describe the frequency and spectrum of cutaneous AEs linked with pembrolizumab and their possible correlation with treatment response.

Synergy of molecular targeted approaches and immunotherapy in melanoma: preclinical basis and clinical perspectives.

Introduction: Targeted therapy and immunotherapies are the novel pharmacologic treatment strategies for metastatic melanoma. BRAF and MEK inhibitors effectively block the hyperactivation of the MAPK pathway in BRAF mutant melanomas and also have several other effects on melanoma cells and on the immune response. The aim of this work is to discuss the rationale, evidence and perspectives of approaches combining target and immunotherapy against melanoma.

Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma.

About one-third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS-driven malignancies barely affect overall survival.

Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma.

Background: BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events.

Objective: We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens.

Methods: We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib).

Mutant NRASQ61 shares signaling similarities across various cancer types--potential implications for future therapies.

Oncogenic mutations in the Neuroblastoma Rat Sarcoma oncogene (NRAS) are frequent in melanoma, but are also found in several other cancer types, such as lung cancer, neuroblastoma and colon cancer. We designed our study to analyze changes in NRAS mutant tumor cells derived from malignancies other than melanoma. A variety of small molecule inhibitors as well as their combinations was tested in order to find beneficial inhibitory modalities in NRASQ61mutant lung cancer and neuroblastoma cell lines.

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastases in melanoma patients.

Background: Interleukin-2 (IL-2) treatment for patients with metastatic melanoma has shown remarkable durable responses. Systemic administration of IL-2 may cause severe side effects, whereas local administration is considered to be a safe alternative. The lungs are common sites of metastases in melanoma patients causing considerable respiratory problems.

NRAS mutant melanoma--undrugable?

Mutations in the three rat sarcoma (RAS) family members NRAS (neuroblastoma-RAS), HRAS (Harvey-RAS) and KRAS (Kirsten-RAS) are found in one third of human cancers. Among the first oncogenes discovered in cutaneous melanoma was NRAS, which is mutant in up to 20% of tumors causing aberrant signaling in several downstream cascades. Despite, being a highly relevant therapeutic target, design of small molecules selectively inhibiting mutant NRAS in melanoma, to date, remains an unsolved challenge.