Transforming therapy for Acral and Mucosal Melanoma Using RAS(ON) Inhibitors  

Acral and mucosal melanomas(A&MM) are rare but aggressive types of melanoma, making up less than 5% of all cases. Unlike the more common type of melanoma, which develops on sun-exposed skin, A&MM arise in areas not typically exposed to the sun—such as the palms, soles, under the nails (acral melanoma), or in mucous membranes like the mouth, nose, and genitals (mucosal melanoma). These cancers follow a different genetic path and do not respond well to standard treatments, making them particularly difficult to treat. Research has shown that many A&MM tumors have mutations that activate a key cellular pathway known as the RAS signaling pathway, which drives cancer growth. However, there are currently no effective targeted treatments for these patients.

A new class of drugs, called RAS(ON) inhibitors, has been developed to block the activity of RAS, offering a potential breakthrough for patients with RAS-driven cancers. Early studies suggest that these drugs could be effective in slowing tumor growth. In my lab research, I tested a RAS(ON) inhibitor on tumor models derived from two patients—one with acral melanoma and one with mucosal melanoma. While the tumors initially shrank in response to the drug, which is a great win for this challenging cancer type, they later became resistant, meaning the treatment stopped working. This indicates that while RAS(ON) inhibitors hold great promise, we need to understand how resistance develops and find ways to prevent or overcome it. This study has two main goals. First, I will test RAS(ON) inhibitors on a larger set of patient-derived tumor models grown in mice to determine which types of A&MM are most likely to respond. Second, I will investigate how resistance to these drugs develops by analyzing genetic changes in tumors before and after they stop responding. By identifying the biological mechanisms that allow the cancer to escape treatment, I aim to discover combination therapies that can enhance the effectiveness of RAS(ON) inhibitors. The results of this research will provide valuable insights into how A&MM can be better treated, guiding the development of new, more effective therapies. Ultimately, this work aims to bring new hope to patients with these rare and challenging melanomas by advancing precision medicine approaches tailored to their unique cancer biology.