Subset Of Melanomas Research Articles

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes.

Despite recent advances in targeted and immune-based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A-replete exosomes, but not RAB27A-knockdown exosomes, indicating that RAB27A is responsible for the generation of pro-invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro-invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma.

Bioenergetic modulation with the mitochondria uncouplers SR4 and niclosamide prevents proliferation and growth of treatment-naïve and vemurafenib-resistant melanomas.

BRAF mutations are detected in >50% of all melanomas. These mutations impair the LKB1-AMPK signaling, an important metabolic pathway associated with cell growth, proliferation and survival. Melanoma patients with BRAF mutations are usually treated with BRAF inhibitors such as vemurafenib, but responses are short-lived as drug resistant tumors metabolically switch to mitochondrial oxidative phosphorylation (OXPHOS) to escape metabolic stress-induced BRAF inhibition. Additionally, a large subset of melanoma utilizes OXPHOS in their metabolism, which can confer de novo resistance to BRAF inhibitors. Therefore, uncoupling of OXPHOS to perturb energy homeostasis and to indirectly stimulate AMPK could be a novel treatment for melanoma and to overcome intrinsic and acquired resistance to BRAF inhibitors. Here, we investigated the effects of SR4 and niclosamide, two small molecule mitochondria uncouplers, on the growth and proliferation of treatment-naïve and vemurafenib-resistant melanomas in vitro and in vivo. SR4 and niclosamide inhibited melanoma proliferation irrespective of BRAF/NRAS status. Melanomas with greater OXPHOS phenotype (higher OCR/ECAR), with LKB1 mutation, or with acquired resistance to vemurafenib displayed greater sensitivity to both uncouplers. More importantly, SR4 and niclosamide inhibited tumor growth in both treatment-naïve and vemurafenib-resistant xenograft mice models. Mechanistic studies indicate both uncouplers induced energetic stress, modulated the AMPK-mTOR pathway, and promoted apoptosis without affecting MEK-ERK MAPK signaling. These results suggest that uncouplers such as SR4 and niclosamide may be useful as first line treatment against melanoma regardless of BRAF/NRAS status, and as an adjuvant therapy for patients failing MAPK inhibitors.

Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma

Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here wehave investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl3-hydroxylase family exemplified by Leprel1 and Leprel2 is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a subset of melanomas, the collagen prolyl 4-hydroxylase familymembers P4HA1, P4HA2, and P4HA3 are often overexpressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumor suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation, and particularly invasiveness, of melanoma cells. Pharmacological inhibition with multiple selective collagen prolyl 4-hydroxylase inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together,our data identify the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibitionof collagen prolyl 4-hydroxylase is an attractive strategy to reduce the invasive properties of melanoma cells.

DEVELOPMENT AND APPLICATION OF A HIGHLY SENSITIVE PNA CLAMP PCR ASSAY FOR DETECTION OF NRAS MUTATIONS IN MELANOMA USING TISSUE AND CFDNA

Melanoma is known to be one of the common cutaneous cancers worldwide. NRAS mutations are found in 15%–20% of melanomas. Non-NRAS-mutant subset of melanoma is less aggressive and associated with higher outcomes in comparison to NRAS- mutant melanoma. New treatment methods for this subset might be developed with improved understanding of NRAS-mutant melanoma. Therefore, a highly sensitive technique for detection of NRAS mutation in melanoma is imperative. The aims of this research were to develop a highly sensitive PCR assay to detect low tumour cell percentage in formalin fixed paraffin embedded (FFPE) tissue and plasma. The assay was developed on stable cell lines containing NRAS (codon 61) mutations. Peptide nucelic acide (PNA) Clamp PCR was used for the selective amplification of DNA target sequences. Total DNA was extracted from 48 FFPE tissues and 20 blood plasma (14 matched) stage II-IV tumours and screened for NRAS mutations. PNA Clamp PCR on FFPE tissue showed 25% (n=12) NRAS mutant of which p.Q61R c.182A>G was the most frequent. Sample cases were independently tested. For NRAS Circulating cell free DNA (cfDNA) analysis only one case was mutated. This demonstrates an innovative and highly sensitive technique for the detection of the common driver mutations in melanoma using exceptionally low tumour burden samples, representing a useful tool for future research and clinical application.

P17 - PGC1a at the Nexus of Cancer Stem Cell Fates

Cancer cells reprogram their metabolism using different strategies to meet anabolic demands to maintain growth and survival. Defining the molecular and genetic determinants of these metabolic programs, including ROS metabolism, is critical to successfully exploit them for therapy. PGC1a is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress and reprograms metabolism to influence drug sensitivity and survival. For example, a subset of melanomas is highly dependent on PGC1a and activates a powerful ROS detoxification capacity that enables survival. Interfering with the ROS detoxification system provides important vulnerabilities of melanoma cells. Importantly, PGC1a is also linked to mitochondrial heterogeneity that allows selective outgrow of cells, both during natural selection and drug-targeted resistance, that exhibit an invasive and aggressive phenotype. Mechanistically, PGC1a establishes a series of transcriptional networks that execute cellular functions including survival and invasion that are central to melanoma progression and therapy responses. In addition, PGC1a also maintain metabolic-dependent epigenetic states that are essential to melanoma progression. As it relates to ROS detoxification capacities these networks are associated with genes that allowed cell reprogramming and survival. The mitochondrial heterogeneity defines different ROS detoxification phenotypes, however the implication of these unique phenotypes to melanoma progression is unknown, but it is likely to impact the fate of melanoma cells including programs of differentiation, growth, survival and invasion.

LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma.

Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, which drives proliferation. The treatment of KIT-mutant GIST has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI) are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. To overcome the problem of KIT TKI resistance, we sought to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosine kinome siRNA screen. From this screen, we identified lemur tyrosine kinase 3 (LMTK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells. We find that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells. Silencing of LMTK3 decreased cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines. Notably, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resistant KIT secondary mutations. Furthermore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model. Our data suggest the potential of LMTK3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKIs.

Abstract 1304: Whole-exome analysis of 1,135 melanomas reveals new significantly mutated cancer genes and copy number alterations

Abstract Introduction: Identifying driver mutations and significantly mutated genes (SMGs) is critical to characterize therapeutic targets and understand biological subtypes. Past studies in melanoma have identified ~20 SMGs and 4 genomic subtypes (BRAF, NRAS, and NF1, and triple wildtype). Critically, these studies have been powered to detect SMGs only at a frequency of >~10%. However, clinically targetable drivers can occur at much lower frequencies (e.g. ALK-rearrangmenet in lung cancer). Thus, we hypothesized that a uniform meta-analysis of all publicly available melanoma whole exome sequences would provide power to identify clinically SMGs not previously associated with melanoma. Methods: We assembled and uniformly analyzed a cohort of 1,135 tumor and matched germline primary and metastatic non-uveal melanoma whole exomes. All samples were realigned to hg19 using the Picard best practice realignment pipeline. These samples passed several QC metrics that included coverage (DepthOfCoverage, 50X tumor and 20X normal), cross sample contamination (ContEst, < 5%), tumor purity (FACETS, > 20%), and tumor-in-normal (deTiN, < 30%). Mutational significance analysis was performed using MutSigCV2 followed by filtering via biological priors using OncoKB. CNA profiles were generated using GATK4 best practices pipeline. Results: We identified 77 SMGs (MutSig q < 0.1) that were implicated in either melanoma or other cancer types according to OncoKB's curated list of 1,018 cancer genes, some of which that have not been considered SMGs or previously reported in melanoma. Novel genes were involved in immune response [B2M (1.7%) and PTPRC (12.1%)], DNA damage checkpoints [MDC1 (7.5%)], negative regulation of the MAPK pathway [CBL (4.6%)], MYC suppression [MGA (9.4%)], and the PI3K/AKT pathway [PIK3CA (3.4%) and PIK3CB (3.5%)]. Within the “triple-wt” subset of melanomas (n=212), we identified additional SMGs including IDH1, SF3B1, CTNNB1, and MAPK2K1 present in 3-5% of tumors, suggesting additional potential therapeutic targets. Copy number profiles of the cohort were consistent with previous findings. By increasing the resolution from cytobands to 1Mb regions, we identified a 1Mb region in chromosome 3 (chr3:138Mb-139Mb) that was enriched in amplifications (29.2%). Genes in this region include MRAS, PI3KCB, FOXL2, and FAIM. Conclusion: Through assembly and uniform analysis of the largest melanoma whole exome cohort to date, we identified significantly mutated known cancer genes not previously associated with the disease, and identified additional drivers within an incompletely characterized subtype of melanoma. This also enabled us to find genome regions enriched in copy number alterations. Taken together, our findings may inform the additional classification of melanoma and identification of novel drivers to shed light on biological subtypes and identify potential therapeutic targets. Citation Format: Jake R. Conway, David Liu, Stephanie Wankowicz, Amaro Taylor-Weiner, Felix Dietlein, Eliezer Van Allen. Whole-exome analysis of 1,135 melanomas reveals new significantly mutated cancer genes and copy number alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1304.

Abstract 2304: In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms

Abstract Targeting cyclin dependent kinases 4 and 6 (CDK4/6) represents a viable therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor in different genetic subsets of melanoma. However, continuous dosing of MEK inhibitor (MEKi) plus CDK4/6 inhibitor (CDK4/6i) elicits toxicities in patients. Utilizing an in vivo E2F reporter system, we analyzed the efficacy of MEKi plus CDK4/6i schedules in a quantitative and temporal manner. Continuous MEKi with intermittent CDK4/6i led to more complete responses as compared to either continuous CDK4/6i with intermittent MEKi or intermittent dosing of both drugs. Nevertheless, some tumors acquired resistance. Phospho-proteomic analysis of resistant tumors revealed increased phosphorylation of ribosomal S6 protein (RPS6). These data were supported by staining of patient biopsies from clinical trials, which also indicated that high phospho S6 levels may serve as a predictor of response to CDK4/6i plus targeted inhibitors. Enhanced phospho S6 provided a therapeutic window for the mTORC1/2 inhibitor, AZD2014, in MEKi plus CDK4/6i-resistant tumors. Mechanistically, aberrant regulation of NRAS was associated with resistance and sufficient to mediate resistance. This study highlights the use of an in vivo reporter model for optimization of schedules and supports targeting the mTORC1/2-S6 pathway as a salvage option to overcome MEKi plus CDK4/6i resistance. Citation Format: Jessica Teh, Phil F. Cheng, Timothy J. Purwin, Neda Nikbakht, Prem Patel, Inna Chervoneva, Ines Keibler, HooKim Kim, Michael A. Davies, Lawrence N. Kwong, Mitch P. Levesque, Reinhard Dummer, Andrew E. Aplin. In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2304.

Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo.

Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo Here, we have investigated the molecular basis of this activity.Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines.Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumor growth in vivo In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S-phase cell-cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumors appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i.Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumors, and may be a useful marker of replication stress in vivoClin Cancer Res; 24(12); 2901-12. ©2018 AACR.

Characterization and spatial localization of the tumor immune microenvironment in metastatic uveal melanoma.

9570Background: Uveal melanoma (UM) is a rare subset of melanoma that is resistant to immune checkpoint blockade. High density of macrophages (Mϕ) and TILs is associated with poor prognosis in prim...

1243 High Rab27a expression is associated with poor melanoma prognosis and promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes

Despite recent advances in targeted and immune-based therapies, metastatic melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis are critical to identify new therapeutic strategies and improve treatment strategies and patient outcomes. Here, using clinical samples, we identified that Rab27a was overexpressed in a subset of melanomas, which correlated with poor survival. To further dissect the function of Rab27a in melanoma, we performed CRISPR-knockout and shRNA-knockdown of this gene in melanoma cell lines. We demonstrated that Rab27a loss inhibited proliferation, colony formation, 3D spheroid invasion and motility in vitro, as well as spontaneous metastasis in vivo. The reduced invasion phenotype observed with Rab27a knockdown was rescued by Rab27a-replete exosomes, indicating that exosomes drive Rab27a-mediated invasion. Further studies revealed that while Rab27a loss did not alter the number of exosomes secreted, there were changes in exosome morphology and the abundance of exosomal proteins associated with cancer cell migration and metastasis. These findings expand on a growing body of literature indicating important roles for Rab27a in regulating cancer cell biology, and further highlights its potential to be utilized as a clinical prognostic marker or therapeutic target in melanoma.

Improving classification of melanocytic nevi: Association of BRAF V600E expression with distinct histomorphologic features

A subset of melanomas carrying a B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) V600E mutation, which is the most common targetable mutation in melanoma, arise in association with a melanocytic nevus that is also harboring a BRAF V600E mutation. The detailed histomorphologic characteristics of nevi positive for BRAF V600E have not been systematically documented. To identify histomorphologic features correlating with BRAF V600E status in nevi. We retrospectively identified melanocytic nevi from our laboratory reporting system. We performed a histomorphologic analysis and analysis of BRAF V600E expression by immunohistochemistry. Thirteen nevi (14.8%) were negative and 76 (86.4%) were positive for BRAF V600E. The nevi positive for BRAF V600E were predominantly dermal (predominantly dermal growth in 55.3% of nevi positive for BRAF V600E and 15.4% of nevi negative for BRAF V600E [P=.01]) and showed a congenital growth pattern (congenital growth pattern in 51.3% of nevi positive for BRAF V600E and 15.4% of nevi negative for BRAF V600E [P=.02]). Compared with nevi negative for BRAF V600E, those that were positive for BRAF V600E often exhibited predominantly nested intraepidermal melanocytes, larger junctional nests, abrupt lateral circumscription, and larger cell size. Architectural disorder and inflammatory infiltrates were seen more often in nevi negative for BRAF V600E. BRAF sequencing of a subset of nevi confirmed the immunohistochemical results. Limitations include the study's retrospective design and the small sample size of nevi negative for BRAF V600E. BRAF V600E is associated with distinct histomorphologic features in nevi. These features may contribute to improving the accuracy of classification and diagnosis of melanocytic neoplasms.

Mucosal Melanoma: a Literature Review.

Mucosal melanoma is of great interest due to its aggressive behavior and less favorable prognosis. The literature is mainly case reports and case series. Here, we will collect the knowledge on mucosal melanoma from the last decade and review the literature. The main focus is being site-specific clinical features, treatment, and prognosis. The use of immunotherapy gain ground as for others subsets of melanoma. Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in mucosal melanoma have been evaluated in recent studies. Clinical trials are ongoing. The etiology of mucosal melanomas remains unknown. Head and neck mucosal melanomas are most common. Wide excision surgery is the treatment of choice. The effect of adjuvant therapy on survival remains questionable due to the limited knowledge. Radiotherapy seems to give better local control. The overall five-year survival rate for mucosal melanomas is 0-45%. Recent data indicates that this may be improved by the immunotherapy in the years to come.

DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation.

Immunotherapy offers new cancer treatment options, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune checkpoint blockade, suggesting the presence of yet-to-be characterized immune suppressive mechanisms. Here we report that APC-loss in intestinal tumor cells or PTEN-loss in melanoma cells upregulates the expression of dickkopf-2 (DKK2), which, together with its receptor LRP5, constitutes an unconventional mechanism for tumor immune evasion. DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5 but independently of LRP6 and the Wnt-β-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates natural killer (NK) and CD8+ cells in tumors, impedes tumor progression, and cooperates with PD-1 blockade. Thus, we have identified a previously unknown tumor immune suppressive mechanism and immunotherapeutic targets particularly relevant for CRCs and a subset of melanomas.

Treatment of uveal melanoma: where are we now?

Uveal melanoma, a rare subset of melanoma, is the most common primary intraocular malignancy in adults. Despite effective primary therapy, nearly 50% of patients will develop metastatic disease. Outcomes for those with metastatic disease remain dismal due to a lack of effective therapies. The unique biology and immunology of uveal melanoma necessitates the development of dedicated management and treatment approaches. Ongoing efforts seek to optimize the efficacy of targeted therapy and immunotherapy in both the adjuvant and metastatic setting. This review provides a comprehensive, updated overview of disease biology and risk stratification, the management of primary disease, options for adjuvant therapy, and the current status of treatment strategies for metastatic disease.

HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma.

Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here, we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo-derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat in 2D and 3D culture systems synergistically induced caspase-dependent apoptotic cell death. Key changes induced by HDAC inhibition included decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases, and cell line dependent upregulation of pro-apoptotic BIM or NOXA together with reduced expression of anti-apoptotic proteins. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance mechanisms are due to activation of MAPK-independent pathways.

Super-enhancers define a proliferative PGC-1\u03b1-expressing melanoma subgroup sensitive to BET inhibition

Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene. BET inhibitor treatment prevented this interaction, leading to a dramatic reduction of PGC-1α expression. Accordingly, BET inhibition diminished respiration and mitochondrial function in cells. In vivo, melanoma models with high PGC-1α expression strongly responded to BET inhibition by reduction of PGC-1α and impaired tumor growth. Altogether, our findings identify epigenetic regulatory elements that define a subset of melanomas with high sensitivity to BET inhibition, which opens up the opportunity to define melanoma patients most likely to respond to this treatment, depending on their tumor characteristics.

ERRα Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1α-Elevated Melanomas.

The uncontrolled growth of tumors provides metabolic dependencies that can be harnessed for therapeutic benefit. Although tumor cells exhibit these increased metabolic demands due to their rapid proliferation, these metabolic processes are general to all cells, and furthermore, targeted therapeutic intervention can provoke compensatory adaptation that alters tumors' characteristics. As an example, a subset of melanomas depends on the transcriptional coactivator PGC1α function to sustain their mitochondrial energy-dependent survival. However, selective outgrowth of resistant PGC1α-independent tumor cells becomes endowed with an augmented metastatic phenotype. To find PGC1α-dependent components that would not affect metastasis in melanomas, an unbiased proteomic analyses was performed and uncovered the orphan nuclear receptor ERRα, which supports PGC1α's control of mitochondrial energetic metabolism, but does not affect the antioxidant nor antimetastatic regulatory roles. Specifically, genetic or pharmacologic inhibition of ERRα reduces the inherent bioenergetic capacity and decreases melanoma cell growth, but without altering the invasive characteristics. Thus, within this particularly aggressive subset of melanomas, which is characterized by heighted expression of PGC1α, ERRα specifically mediates prosurvival functions and represents a tangible therapeutic target.Implications: ERRα, a druggable protein, mediates the bioenergetic effects in melanomas defined by high PGC1α expression, suggesting a rational means for therapeutic targeting of this particularly aggressive melanoma subtype. Mol Cancer Res; 15(10); 1366-75. ©2017 AACR.

Midkine and Melanoma Metastasis: A Malevolent Mix

Using an invivo reporter for lymphangiogenesis, a recent study in Nature from Olmeda etal. (2017) describes a new subset of melanomas that induce systemic pre-conditioning of distant organs for formation of tumor metastatic niches, and identifies the responsible factor as the pleiotropic cytokine midkine.

NRAS-mutant melanoma: current challenges and future prospect.

Melanoma is one of the most common cutaneous cancers worldwide. Activating mutations in RAS oncogenes are found in a third of all human cancers and NRAS mutations are found in 15%–20% of melanomas. The NRAS-mutant subset of melanoma is more aggressive and associated with poorer outcomes, compared to non-NRAS-mutant melanoma. Although immune checkpoint inhibitors and targeted therapies for BRAF-mutant melanoma are transforming the treatment of metastatic melanoma, the ideal treatment for NRAS-mutant melanoma remains unknown. Despite promising preclinical data, current therapies for NRAS-mutant melanoma remain limited, showing a modest increase in progression-free survival but without any benefit in overall survival. Combining MEK inhibitors with agents inhibiting cell cycling and the PI3K–AKT pathway appears to provide additional benefit; in particular, a strategy of MEK inhibition and CDK4/6 inhibition is likely to be a viable treatment option in the future. Patients whose tumors had NRAS mutations had better response to immunotherapy and better outcomes than patients whose tumors had other genetic subtypes, suggesting that immune therapies – especially immune checkpoint inhibitors – may be particularly effective as treatment options for NRAS-mutant melanoma. Improved understanding of NRAS-mutant melanoma will be essential to develop new treatment strategies for this subset of patients with melanoma.