LCC12 as a potential modulator of plasticity and survival in BRAFi-resistant melanoma

• Grant number: 25/26472-3
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: March 01, 2026
• End date: June 01, 2026
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Manuela Garcia Alves
• Supervisor: Corine Bertolotto
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Université Côte d'Azur, France
• Associated to the scholarship: 24/13027-9 - CNOT7 as a possible therapeutic target for overcoming drug resistance in melanoma, BP.IC

Abstract

Melanoma is the deadliest type of skin cancer. Its incidence has steadily risen due to increased ultraviolet (UV) exposure, which induces somatic mutations in melanocytes, leading to uncontrolled proliferation and genetic instability. The MAPK pathway, particularly the Ras/Raf/MEK/ERK cascade, is central to melanoma pathogenesis, being hyperactivated in up to 90% of tumors, with frequent BRAF and NRAS mutations driving tumor growth. Despite advances with targeted therapies against BRAF-mutated tumors and immune checkpoint inhibitors, resistance often develops, leaving many patients without effective treatment. Resistance arises from melanoma cells' high heterogeneity and plasticity, which allows the selection of drug-resistant clones and the establishment of transient resistant states. Metallodrugs, particularly copper-based compounds, have emerged as promising alternatives. Copper is an essential cofactor for enzymes involved in proliferation, energy generation, and antioxidant defense, and its concentration is tightly regulated intracellularly. Melanoma cells exhibit altered metabolism and are highly sensitive to oxidative stress and fluctuations in copper levels, making copper complexes, especially di-nuclear ones, potential therapies with selective toxicity. Our group, in collaboration with Prof. Corine Bertolotto at Université Côte d'Azur, has investigated the di-nuclear copper (II) complex LCC12, which demonstrates cytotoxicity against parental and therapy-resistant melanoma cells, while promoting redifferentiation toward a more differentiated, less invasive and treatment-sensitive phenotype. This approach aims to provide mechanistic insights into LCC12 action and improve our understanding of its potential role in overcoming drug resistance (AU)