The role of adenosine kinase in human Melanoma progression and resistance

• Grant number: 20/14878-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2021
• End date: May 17, 2025
• Field of knowledge: Biological Sciences - Genetics
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Julia Rezende da Silva
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/04926-6 - Melanoma and chemoresistance: in vitro and in silico models to exploit therapeutic targets, AP.TEM
• Associated scholarship(s): 23/01126-0 - Exploring tumor evolution from primary to metastatic cancers: a multi-omics profile, BE.EP.DD

Abstract

Melanoma is a malignant neoplasm that originates from melanocytes and although it corresponds to only 3% of skin cancers, it is responsible for 80% of deaths. This is because metastatic Melanoma is refractory to conventional and targeted therapies and because it quickly acquires resistance to specific inhibitors of mutated proteins in the MAPK pathway, such as BRAF. In silico screening studies developed by our research group Skin Biology (FCF-USP), using TCGA and GEO databases, identified the adenosine kinase gene (ADK) with different expressions between nevus and invasive Melanoma. ADK is a key enzyme in the regulation of purine metabolism and exerts a great influence on adenosinergic pathways. Research has shown a significant relationship between ADK activity and cell growth and proliferation, but its importance has never been explored in Melanoma. Therefore, considering the search for effective targeted therapies for patients with Melanoma, the current master's project (FAPESP 2018/20665-0) aimed to investigate ADK gene and protein expressions, as well as to inhibit this gene via shRNA in human Melanoma cells. In view of promising results of alteration in ADK expression as the Melanoma progresses, this doctoral project consists of exploring and evaluating the molecular mechanisms related to this gene that may influence the proliferation, survival, invasion and resistance of human Melanoma cells. In parallel, we will also investigate whether gene (shRNA) or pharmacological (ADK inhibitor - ABT-702) ADK inhibition is able to modulate the expression of key genes that are related to Cancer and chemoresistance, exploring these changes through array panels. Therefore, continuing to investigate the impacts of ADK inhibition may contribute to better understanding the mechanisms of tumorigenesis in human Melanoma, contributing to a potential identification of a new therapeutic target. (AU)