CNOT7 as a possible therapeutic target for overcoming drug resistance in melanoma

• Grant number: 24/13027-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2024
• End date: November 30, 2025
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Manuela Garcia Alves
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Melanoma is considered the most aggressive type of skin cancer and the one with the worst prognosis because of its high metastatic and proliferative capacity. Its carcinogenic process is related to the emergence of mutations on somatic genes related to cell cycle control, especially the MAPK pathway, in which BRAFV600E is the most frequent mutation. The development of immunotherapy and targeted therapies with BRAF and MEK inhibitors represented importante advances in the way of establishing effective therapies against melanoma. However, the emergence of resistance by selection of resistant phenotypes and tumor recurrence after treatment represent challenges to establish a better prognosis for the disease. In this way, it is necessary to search for new therapies and strategies that may overcome these resistance mechanisms. Gene pairs that present Sintethic Lethal interactions, property in which depletion of the pair leads to cell death but individual depletion of the gene does not, are a relevant study approach, since melanoma presents a high mutation burden and this ways it is possible to target tumor cells in a more selective way. In this case, the CNOT7 gene, which belongs to the CCR4-NOT deadenylation complex, emerges as an interesting target, since it is relatively well expressed in skin, has differentiated expression in healthy and tumor tissue and had its expression related to tumor progression and resistance to targeted therapies in other types of cancer. Therefore, the present project aims to evaluate the potential of the CNOT7 gene as a target to minimize resistance to anti-melanoma treatments by studying its role in the carcinogenesis and progression of melanoma using cell viability, migration and invasion tests. RT-qPCR, Western Blotting in a two-dimensional experimental model