Abstract 1616: Elucidating the role of PI3K lipid effectors in BRAF mutant melanoma

Abstract Metastatic melanoma accounts for the highest number of skin cancer deaths, and while current treatments for this disease have progressed significantly in recent years, stage IV melanoma currently has only a 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 therapies for 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 which 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; however, pharmacological inhibitors of AKT 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, which is dependent on functional kinase activity. Based on these preliminary results, we seek to determine if the PI3K pathway depends solely on AKT signaling for its role in melanoma initiation and progression. Dysregulation of the PI3K lipid signaling cascade in melanoma is conventionally believed to occur through activation of AKT, and we have previously shown that either loss of PTEN or mutationally activated PI3K cooperates with mutant BRAF to promote melanoma formation. However, it has not been shown if constitutively active AKT alone is able to substitute for this effect. Further research will elucidate the role of AKT in the initiating stages of melanoma and provide a more thorough understanding of the PI3K/AKT signaling pathway in promoting BRAF mutant melanomagnesis. Citation Format: Gennie Parkman, Joseph Cho, Sheri Holmen, Martin McMahon. Elucidating the role of PI3K lipid effectors in BRAF mutant melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1616.