The Study of the Mechanisms and Therapeutic Effects of Ssri Antidepressants Combined with Braf/Mek Inhibitors in Melanoma

Malignant melanoma is the most lethal skin cancer. In Taiwan, the most common melanoma subtypes observed was wild type BRAF (WT-BRAF). There is no target therapy specific for WT-BRAF melanoma nowadays whereas the current treatment of choice remains with surgery, cytokine therapy and chemotherapy. Even though breakthroughs have been made, but the multiple mutational processes and high metastasis is yet to be overcome, leaving the breakthrough of melanoma treatment in a dilemma. Especially the WT-BRAF melanoma treatment is still needed in clinical. Retrospective cohort studies indicated that antidepressants decreased the risk of glioma and colorectal cancer thus suggested the potential of adjuvant therapy in cancer. In our previous study, we have selected several SSRI antidepressant and have found out that Paroxetine (SeroxatR) blocked MAPK pathway, induced mitochondrial damage and specifically activated melanoma cell apoptosis. The in vitro study suggests that paroxetine not only inhibited melanoma growth but also blocked metastasis. The xenograft animal study confirmed paroxetine activated apoptosis pathway and inhibit melanoma growth in vivo. It suggest the paroxetine specifically block melanoma cell viability and abolished melanoma migration/invasion thus indicated the melanoma treatment potential in clinical. Our preliminary study further found out that paroxetine suppressed wild type and mutation type BRAF melanoma cells viability. In addition, paroxetine blocked AKT phosphorylation and suppressed PD-L1 gene expression in wild type and mutation type BRAF melanoma cells. While combined with BRAF inhibitor-Vemurafenib (ZelborafR), paroxetine synergically killed wild type and mutation type BRAF melanoma cells. Significant breakthrough in treating and preventing wild type and mutation type BRAF melanoma may be achieved via the combination of SSRI antidepressant and clinical target therapies. Our study aims to understand more regarding the toxicity and mechanism of action in combination of SSRI antidepressants and target therapy medications. Objectives of this three-year research project are as follow: First year: the evaluation and selection of the drug efficacy and its mechanism. Second year: the evaluation of combination drug efficacy and its mechanism. Third year: animal studies and pre-clinical study evaluation.