Melanoma is the type of skin cancer with the highest metastatic potential, resulting in its high mortality rate. The main mutations in melanoma occur in the MAPKs pathway: 50% of patients have alterations in BRAF; 15-20% in NRAS and mutations in NF1 or triple wild-type tumors account for the remaining cases. Although targeted therapy has revolutionized the treatment for melanoma through the use of BRAF inhibitors, intrinsic or acquired resistance still lead to treatment failure. It appears as though NRAS mutations make for an even more aggressive tumor, which also lack targeted therapy drugs, hence this mutation is linked to worse prognoses. Intratumoral heterogeneity is a consequence of the phenotypic plasticity of melanoma cells, which maintain and switch through phenotypic states determined by MITF levels. This phenomenon is closely related treatment failure. Thus, new targets and alternative pathways must be investigated as potential options for the treatment of patients with NRAS mutations. In this context, hydrogen peroxide plays a central role in redox signaling and it is involved in all Hallmarks of Cancer, from proliferation through metabolism, angiogenesis and avoidance of immune destruction. Moreover, it is able to alter MITF levels. Therefore, due to their high expression and catalytic activity, peroxiredoxins (PRDXs) are the main agents of intracellular hydrogen peroxide detoxification. In addition to their exceptional role in the removal of this oxidant, their oxidation and subsequent inactivation gives hydrogen peroxide a leeway to react with other targets, thereby regulating redox signaling in the cell. As a consequence of this crucial role in controlling hydrogen peroxide, PRDXs are directly involved in several different types of cancer. As a matter of fact, the isoform PRDX2 appears to be epigenetically silenced in some patients and our group has recently shown that it is downregulated in metastatic melanoma patients, reinforcing its involvement in the process of invasion. However, the use of the small molecule PRDX2 inhibitor conoidin A seemed to reduce the proliferation and viability of therapy-resistant gastric cancer cells. Our preliminary data suggest that conoidin A reduces the viability of NRAS mutant melanoma cell lines with doses in the nM-µM range. Having in mind the use of therapies that increase oxidative stress, the lack of treatment options for NRAS mutations and the apparently contradictory role of PRDX2 in different types of cancer, this project aims to explore the effects of inhibiting PRDX2 with conoidin A. It is important to note that this project is a part of a PhD project from our group, from Isabella Noma, that investigates the role of PRDX2 in NRAS mutant melanomas. With these results, we hope to provide an answer for whether the role of PRDX2 in melanoma is connected to its antioxidant activity or to its aforementioned role in regulating redox signaling, and to evaluate the potential of conoidin A as a therapeutic option for patients with NRAS mutations.
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