Targeting Active RAS to Stimulate Antitumor Immunity in Acral Melanoma

Acral melanoma is a rare and understudied subtype of melanoma with few treatment options and poor outcomes. The current standard of care treatment for advanced disease is immunotherapies. However, many patients do not respond to this treatment. The protein, RAS, is a promising target for targeted inhibitor drugs in acral melanoma, as cancer cells frequently have increased activity of this protein. Additionally, acral melanoma tumors often have low levels of patient immune cells that can attack cancer cells. Our short-term goals are to understand the potential for RAS targeted inhibitor use in acral melanoma and identify the effects on interactions between cancer cells and surrounding immune cells.

We tested if RMC-7977, a recently developed RAS inhibitor currently in clinical trials, works in acral melanoma cell lines with mutations in the RAS gene. We found that RMC-7977 stops growth and causes death of cancer cells via pyroptosis, a form of cell death that recruits and activates immune cells that can clear tumors. Through this proposal, we aim to further understand how pyroptosis occurs in acral melanoma cells treated with RMC-7977. Additionally, we will study how RMC-7977 alters interactions between tumor cells and surrounding immune cells. We expect to show that RMC-7977 may be an effective therapeutic strategy for metastatic acral melanoma patients.