Metastatic melanoma is an aggressive form of cancer responsible for the majority of skin cancer related deaths. While treatment for metastatic melanoma has improved in recent years with the introduction of targeted therapies and immunotherapies, the five-year survival rate for stage IV melanoma remains only 15-20%. To address the need for alternative options for melanoma treatment, we have begun exploring use of an engineered human enzyme called methionine-gamma-lyase (hMGL). Many cancers, including melanoma, have a high requirement for methionine in comparison with non-cancerous cells. The hMGL enzyme works to exploit this difference by degrading extracellular L-methionine resulting in cancer cell starvation. The hypothesis tested in this research is that the systemic depletion of L-methionine using hMGL will provide significant benefits for melanoma treatment alone or in combination with other therapeutic agents. Treatment of several melanoma cell lines (A375, Hs294T, Skmel28, and B16F10) with various concentrations of hMGL demonstrated that L-methionine depletion reduced survival and led to a G2 cell cycle arrest. To investigate the mechanism of action, analyses of melanoma cells treated with hMGL have shown that signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation is significantly reduced. Additionally, hMGL treatment leads to activation of the uncharged tRNA amino acid sensing pathway as shown by an increase in p-eIF2α and Sestrin 2 and an increase in autophagy shown by a decrease in p-ULKSer757 and an increase in cleaved LC3B. Because L-methionine depletion affects levels of glutathione through reduction of cysteine synthesis, preliminary experiments were conducted to evaluate hMGL treatment combined with a thioredoxin reductase inhibitor. This combination, targeting two different intracellular antioxidant pathways, resulted in synergistic inhibition of survival in multiple melanoma cell lines. The current data support the hypothesis that L-methionine depletion using hMGL may have therapeutic efficacy either alone or in combinations for melanoma treatment. Research funded by CPRIT grant RP180590.

Citation Format: Carly S. Wilder, Achinto Saha, George Georgiou, Everett Stone, John DiGiovanni. Systemic depletion of L-methionine with an engineered human enzyme for the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2996.