Abstract: The inventors' working hypothesis relies on the original observations that mesenchymal MAPKi resistant cells display markers of fibrosis, acquire a myofibroblast-like phenotype and extracellular matrix (ECM) remodelling activities. In addition to increased remodelling of the ECM, pro-fibrotic responses induced by MAPK-targeted therapy include enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues and the establishment of an inflammatory microenvironment that contribute to therapy escape. The inventor's reason that approaches aimed at manipulating this abnormal fibrotic-like response induced by targeted therapy may represent rationale combination strategies to normalize the fibrous stroma, enhance drug efficacy and overcome resistance in BRAE mutant melanoma. Here the inventors investigated the impact of Nintedanib, an EMA/FDA-approved anti-fibrotic drug, as a repurposed drus in combination with targeted therapy on melanoma cell viability and tumor growth.

Abstract: Accordingly, the invention relates to a method for predicting the survival time of a subject suffering from melanoma by quantifying the expression level of PSMD14 in a biological sample.

Abstract: The present invention relates to a method and composition for treating melanoma, aggressive/invasive melanoma, metastatic melanoma or melanoma resistant. More particularly, inventors have shown that high expression of PTX3 correlates with melanoma invasiveness and with a poorer survival rate in metastatic melanoma patients. PTX3 knockdown inhibited melanoma cell migration, invasion, lung metastasis, and NF?B signaling pathway. An addition of melanoma-derived or recombinant PTX3, or overexpression of PTX3 enhanced motility of low migratory cells. Finally, they found that TLR4 and MYD88 knockdown or targeting inhibited PTX3-induced melanoma cell migration, suggesting that PTX3 functions through a TLR4/NF?B-dependent pathway.

Abstract: Inventors have shown that targeting DDR1 and DDR2 collagen receptors by Imatinib resensitizes melanoma tumors to BRAFV600E to targeted therapy and normalizes the fibrotic stromal reaction. These findings provide the rationale to combine Imatinib (or other DDR inhibitors) and MAPK-targeting agents to disrupt the influence of the matrix microenvironment in order to delay or prevent the emergence of therapy-resistant cells. They have shown that inhibition of DDR1 and DDR2 kinase activities by Imatinib suppressed the protection of melanoma cells against Vemurafenib (BRAFi) and Trametinib (MEKi) co-drugging and led to cell cycle arrest and cell death. Similar biochemical cell cycle and apoptotic events were promoted in presence of Nilotinib. They validated this anti-tumor activity of Imatinib combined with Vemurafenib in a pre-clinical xenograft model of melanoma and showed that targeting DDR1/2 signaling delays tumor relapse.

Abstract: The present invention relates to a method and composition for treating melanoma. More particularly, inventors have shown that high expression of USP14 correlates with melanoma progression and with a poorer survival rate in metastatic melanoma patients. Then, they have shown that an inhibition of ubiquitin-specific peptidase 14 (USP14) by siRNAs and pharmacological inhibitors (b-AP15, WP1130 and HBX41108), the cell proliferation of melanoma cell drastically decreased. They have also shown that melanoma treatment with pharmacological inhibitors can overcome resistance to drugs targeting oncogenic BRAF. Accordingly, the invention relates to a method for predicting the survival time of a subject suffering from melanoma by quantifying the expression level of USP14 in a biological sample and to a method of treating melanoma and resistant melanoma by using the inhibitors of USP14.