Metastatic melanoma accounts for the highest number of skin cancer deaths, and stage IV melanoma currently has only a devastating 15-20% five-year survival rate. This highlights the critical need for new therapeutics to treat this complex disease. The PI3K/AKT pathway and RAS-RAF-MEK-ERK pathway play a major role in melanoma initiation and progression. Mutations in BRAF are found in around 50% of all human melanomas, and although there has been significant success in the development of BRAF mutant melanomas, most patients will experience primary or secondary resistance. Furthermore, mutant BRAF has been shown to be insufficient for melanomagenesis, yet the mechanism by mutationally activated BRAF cooperates with oncogenes and loss of tumor suppressors to promote melanoma tumorigenesis and progression is not well understood. Dysregulated PI3K/AKT signaling is frequently observed concurrently with BRAF mutant melanomas though AKT pharmacological inhibitors have been largely ineffective in clinical trials as single agents. Studies in our lab have shown that there is a discordant effect between pharmacological inhibition and genetic targeting of AKT, suggesting that therapeutic inhibition of this protein kinase is insufficient to block its activity in melanoma. We have shown that genetic knockdown of all three AKT paralogs leads to complete cell lethality in multiple human melanoma cell lines, and overexpression of each of the AKT proteins is able to significantly rescue this deleterious effect, dependent on functional kinase activity. Based on these preliminary results, we seek to answer if the PI3K pathway depends solely on AKT signaling for its role in melanoma initiation and progression. Furthermore, to date, we have also identified additional downstream PI3K lipid binding proteins that may compensate for the inhibition of the AKT signaling axis in this disease. We hypothesize that when AKT is inhibited, there are other PI3K lipid effectors, namely SGK, highly homologous to AKT, that are sufficient for downstream signaling leading to melanoma formation, progression, and metastasis. The validation of these lipid effectors may lead to additional therapeutic targets. Currently, the field lacks effective rational combination MAPK and PI3K pathway-targeted therapeutics to more effectively target BRAF mutated melanomas, and our objective is to uncover the molecular mechanisms of the concurrent activation of these crucial signaling pathways. Results accumulated from the study will lead to further findings that in turn will improve the health of melanoma patients, including expanding the average life span after diagnosis.
Although recent advances have revolutionized the treatment landscape of melanoma in recent years, current therapies are limited by resistance and low response rates. This grant will investigate the co-occurrence of aberrant PI3K and MAPK signaling in the promotion of melanoma initiation, progression, metastasis, and resistance. This study will aim to establish preclinical models that accurately recapitulate human melanoma and provide the foundation for development of rational therapeutic strategies to effectively target BRAF mutated melanoma.
