ETD

• BRAF inhibitors
• pigmentation inhibitors
• Toxicity
• Zebrafish

Cutaneous melanoma is one of the most aggressive skin cancers and arises from melanocytes, the cells responsible for melanin production. The BRAFV600E mutation, present in 40–60% of cases, leads to constitutive activation of the MAPK pathway (RAS/RAF/MEK/ERK), promoting tumor progression. Targeted therapies using BRAF inhibitors (BRAFi), often combined with MEK inhibitors (MEKi), have improved survival and quality of life in patients with BRAFV600E-mutant melanoma. However, acquired resistance typically emerges after a few months of treatment, highlighting the need for improved therapeutic strategies. Our lab has recently shown that melanin may act as a tolerance mechanism to BRAFi/MEKi. Co-treatment with pigmentation inhibitors (PIGMi), which interfere with melanin production pathways, has shown promise in increasing the efficacy of BRAFi in melanoma cell lines. To investigate this in vivo, we use a transgenic zebrafish model expressing BRAFV600E and the neural crest marker crestin:mCherry. In this model, vemurafenib reduces crestin-driven fluorescence, serving as a readout of drug response. My thesis focused on performing a preliminary toxicity screen in crestin:mCherry embryos to identify safe concentrations of the BRAFi Dabrafenib and PIGMi compounds (Apilimod, 4-Butylresorcinol, 5-Iodotubercidin, and ML329), to be later used in combination treatments.