Genetics and epigenetics of cutaneous malignant melanoma: A concert out of tune

Hurk, Karin van den; Niessen, Hanneke E.C.; Veeck, Jürgen; Steensel, M.A.M. van; Hausen, Axel zur; Engeland, Manon van; Winnepenninckx, Véronique

doi:10.1016/j.bbcan.2012.03.011

Cited by 46 publications

(48 citation statements)

References 250 publications

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“…The list of candidate drivers identified in BCTSB13 melanomas (PLX4720-naïve) (Dataset S1) included 56 statistically significant loci (P < 0.05; Materials and Methods) and many wellestablished melanoma driver genes including Cdkn2a and Pten (20,21,(31)(32)(33), as well as candidate drivers such as Atrx and Sox6, which have not previously been described in melanoma. The patterns of T2/Onc transposon insertions in Cdkn2a and Pten ( Fig.…”

Section: Resultsmentioning

confidence: 99%

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Perna

Karreth

Rust

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

127

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BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼80% of BRAF V600 -mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf V618E (analogous to the human BRAF V600E mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf V618E transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes. melanoma | drug resistance | BRAF inhibitors | mouse models T he discovery that ∼50-60% of melanomas carry BRAF V600E point mutations (1) prompted the generation of compounds specifically targeting this hyperactive mutated kinase. One such compound, PLX4032, has shown unprecedented therapeutic efficacy in clinical trials and was therefore FDA-approved for clinical therapy under the name vemurafenib. Despite its remarkable efficacy, almost all patients receiving BRAF inhibitor treatment relapsed after weeks to months of therapy (2-5). Acquired resistance to BRAF inhibitors has since been a major focus of research and two major paths to resistance have emerged: MAPK-dependent and MAPK-independent mechanisms. MAPK-dependent mechanisms primarily involve reactivation of the MAPK pathway to substitute for the inhibition of BRAF V600E. This may be achieved through mechanisms including expression of alternative splicing forms of BRAF V600E

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Section: Resultsmentioning

confidence: 99%

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Perna

Karreth

Rust

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

127

View full text Add to dashboard Cite

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“…In addition to mutations, cutaneous malignant melanoma is characterized by chromosomal gains which include the melanoma oncogenes CDK4, cyclin D1 and microphthalmia-associated transcription factor (MITF), and chromosomal losses which encompass the tumor suppressor genes p15INK4b, p16INK4a, p14ARF, and phosphatase and tensin homolog (PTEN), among others [9]. Epigenetic changes that are implicated in melanoma progression include DNA methylation, non-coding RNAs, and histone modifications [10,11].…”

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confidence: 99%

Developing strategies to predict photodynamic therapy outcome: the role of melanoma microenvironment

et al. 2015

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Melanoma is among the most aggressive and treatment-resistant human skin cancer. Photodynamic therapy (PDT), a minimally invasive therapeutic modality, is a promising approach to treating melanoma. It combines a non-toxic photoactivatable drug called photosensitizer with harmless visible light to generate reactive oxygen species which mediate the antitumor effects. The aim of this review was to compile the available data about PDT on melanoma. Our comparative analysis revealed a disconnection between several hypotheses generated by in vitro therapeutic studies and in vivo and clinical assays. This fact led us to highlight new preclinical experimental platforms that mimic the complexity of tumor biology. The tumor and its stromal microenvironment have a dynamic and reciprocal interaction that plays a critical role in tumor resistance, and these interactions can be exploited for novel therapeutic targets. In this sense, we review two strategies used by photodynamic researchers: (a) developing 3D culture systems which mimic tumor architecture and (b) heterotypic cultures that resemble tumor microenvironment to favor therapeutic regimen design. After this comprehensive review of the literature, we suggest that new complementary preclinical models are required to better optimize the clinical outcome of PDT on skin melanoma.

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“…38 Aberrant acetylation of histones, in particular hypoacetylation, is thought to influence the pathobiology of melanoma by disrupting the same pathways as are affected by mutations and CpG island hypermethylation. 39 In melanoma, gene expression profiles revealed loss of expression of tumor suppressor genes through reversible deacetylation of lysine residues in local histones by histone deacetylases (HDACs). 40 CDKN1A is one such tumor suppressor gene, and expression of its product, p21 cip1 , was upregulated following inhibition of histone deacetylase.…”

Section: Histone Modificationmentioning

confidence: 99%