Functional characterization of CNOT7 and CNOT8 genes in melanoma and their therapeutic potential for synthetic lethality

• Grant number: 25/04597-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Amanda Soares Hirata
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Melanoma, which originates from the malignant transformation of melanocytes, is considered the most aggressive type of skin cancer with a high mortality rate, particularly due to the limitations of current treatments and early resistance. In this context, synthetic lethality (SL) emerges as a promising approach, based on inducing cell death through the simultaneous inhibition of two related genes. The research group of our collaborator Dr. David Adams from the Wellcome Sanger Institute in Cambridge, UK, identified the genes CNOT7/CNOT8 as potential SL candidates in melanoma, lung and pancreatic cancers. These proteins are the catalytic subunits of the deadenylation process in the CCR4-NOT complex, an essential phenomenon for mRNA degradation. Some studies have shown that, in addition to their overexpression, these proteins are involved in the proliferation, metastasis, and resistance of other types of cancers. Pioneering in cutaneous melanoma, the present project aims to characterize the role of CNOT7/CNOT8 proteins in carcinogenesis and chemoresistance through gene deletion using the CRISPR/Cas9 technique in monolayer models with melanoma cell lines and three-dimensional models with reconstructed human skin. The expression of CNOT7/CNOT8 will be evaluated in primary tumor cells from patients, reinforcing the representativeness of the in silico and in vitro findings. In this way, the aim is to validate whether the interaction of these two genes is lethal for cutaneous melanoma and, then, describe the therapeutic potential of the CNOT7 and CNOT8 gene pair for the treatment of chemotherapy-sensitive and resistant melanoma.