Project 458828

Melanoma is the deadliest form of skin cancer, arising from the cancerous transformation of the melanocytes, the pigment producing cells of the skin. In 5-10% of sun-exposed melanoma patients, a recurrent mutation in a key regulator of cellular growth and migration, RAC1 P29S, induces the transformation of melanocytes into cancerous cells, increases tumor growth, and leads to spreading of the cancer throughout the body. Despite this, appropriate treatment strategies for RAC1-mutant melanoma have yet to be identified. We hypothesize that by exploring the cellular changes occurring in melanoma with the RAC1 P29S mutation we will identify new drug targets that specifically kill mutant melanoma cells without affecting healthy cells in the body. The first aim of this project is to investigate proteins that interact more strongly with mutant RAC1 compared to the wildtype, or non-mutant, protein. These strong interactors are suspected to play a pivotal role in RAC1-mutant cellular movement and may represent a target for drug therapy. To examine this relationship further, we will measure the cellular growth, migration and invasion in human cell models expressing mutant RAC1 and lacking expression of the identified interacting partners. The second aim of this project focuses on identifying molecular vulnerabilities of melanoma with the RAC1 mutation, in order to find drugs that can prevent tumor growth. To accomplish this aim, we will use an unbiased genetic screening approach that can identify new and effective druggable protein targets in melanoma. The third aim of this project focuses on utilizing the protein degradation pathways naturally found in cells to increase the destruction of mutant RAC1. In sum, this project focuses on understanding the effect of mutant RAC1 and aims to identify new strategies for the treatment of RAC1-mutant melanoma.