Overcoming chemoresistance in melanoma using a peptide that blocks PI3KB

Skin cancer is the most commonly diagnosed cancer in the US. Although melanoma accounts for only 1% of skin cancers, it causes the majority of deaths. 50% of melanoma tumors contain mutations in the BRAF protein, which causes cells to constantly grow and divide. Drugs that target this growth pathway are effective, but melanomas typically overcome these drugs within one year, often by using alternative pathways to cell growth. One such pathway is through a protein called phosphatidyl inositol 3-kinase (PI3K). Research targeting this pathway has shown variable success. This is in part because subclasses of PI3K, including PI3Ka,ß,d, and ?, have different roles, including in metabolic and immune functions, and inhibition of all PI3K subclasses can have serious side effects. Research by the Sheng Lab and others has demonstrated a key role of PI3Kß specifically in melanoma cells with the BRAF mutation.

As such, our overarching research question explores how targeting PI3Kß specifically will decrease melanoma cell growth in melanomas that have overcome existing drug therapies. The proposed research investigates how inhibiting PI3Kß will affect melanoma cells that are resistant to Dabrafenib/Trametinib, one of the existing melanoma treatment combinations. The Sheng Lab has designed a unique drug, Selective-9 (S9) that blocks PI3Kß only, without affecting other PI3K proteins. We hypothesize that therapy-resistant melanoma cells with high levels of PI3K will show less growth when treated with S9 compared to therapy-resistant melanoma cells with low levels of PI3K. Utilizing existing drug combinations with proven success in treating melanoma is resource-efficient and safe, while inhibiting specific tumor pathways will also create more individualized treatment solutions.