Melanoma represents the most aggressive and the deadliest form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. The therapeutic strategy can include single agents or combined therapies, depending on the patient’s health, stage, and location of the tumor. The efficiency of these treatments can be decreased due to the development of diverse resistance mechanisms. New therapeutic targets have emerged from studies of the genetic profile of melanocytes and from the identification of molecular factors involved in the pathogenesis of the malignant transformation. In this review, we aim to survey therapies approved and under evaluation for melanoma treatment and relevant research on the molecular mechanisms underlying melanomagenesis.

Background: Melanoma accounts for only 1% of all skin malignant tumors; however, it is the deadliest form of skin cancer. Since 2011, FDA (Food and Drug Administration) approved several novel therapeutic strategies, such as MAPK pathway targeted therapies, to treat cutaneous melanoma patients. However, their improvements in overall survival were limited, due to the development of resistance. Methods: In this work, several combinations of therapies, including the metabolic modulator DCA, were tested in melanoma cell lines, considering that MAPK and PI3K/AKT/ mTOR pathways are deregulated and interconnected in melanoma and that the presence of the Warburg effect in melanoma cells may influence the response to therapy. The effect of the treatments was assessed in the proliferation and survival of melanoma cell lines with different genetic profiles. Also, the possibility to overcome resistance to the treatment with vemurafenib was tested. Results: In general, higher decrease in cell viability and cell proliferation and increase in apoptosis were obtained after the combination treatments, comparing with single treatments, in all the studied cell lines. The combination of cobimetinib and everolimus appear to be the best treatment option. The BRAFV600E -vemurafenib resistant melanoma cell line showed to retain sensitivity to both everolimus and DCA. Discussion and Conclusion: Our results suggest that the combination of MAPK pathway inhibitors with mTOR pathway inhibitors and DCA should be considered as therapeutic options to treat melanoma patients, as the combinations potentiated the effects of each drug alone. In a cell line resistant to vemurafenib, we verified that combined MAPK inhibitors with inhibition of mTOR pathway and/or DCA metabolism modulation might constitute possible strategies in order to overcome resistance to MAPK inhibition.

NR2F1, TBX2) restored in vitro enzalutamide sensitivity in CHD1 deleted cells. Independently derived, enzalutamide-resistant, CHD1-deleted subclones expressed elevated levels of 1 or more of these 4 transcription factors. This pattern suggests a state of chromatin plasticity and enhanced heterogeneity, initiated by CHD1 loss, which enables upregulation of distinct sets of genes in response to selective pressure. This concept is further supported by RNA-seq data from a mCRPC patients cohort, in which we examined the co-association of CHD1 levels with each of these four TFs across 212 tumors. Furthermore, we observed increased lineage plasticity in most of the resistant tumors driven by heterogenous resistant driver genes, including the downregulation of luminal lineage transcriptional program and upregulation of genes specify epithelial to mesenchymal transition (EMT).Conclusions: We demonstrated that loss of the chromodomain gene CHD1, a commonly deleted prostate cancer gene, through global effects on chromatin, establishes a state of plasticity that accelerates the development of hormone therapy resistance through heterogeneous activation of downstream effectors.No conflict of interest. 53Poster Discussion Metabolic modulation combined with mTOR pathway inhibition may overcame cutaneous melanoma resistance to MAPK inhibitors treatment