Abstract IA10: Targeting melanoma metabolism to overcome resistance to treatment

Abstract

Abstract Despite adequate oxygen levels, cancer cells undergo anaerobic glycolysis converting glucose to lactate (the Warburg effect). It is now thought that the advantage of this for the cancer cell is that it provides the carbon and nitrogen precursors critical for macromolecule synthesis (amino acids, nucleotides, fatty acids) while still providing an adequate supply of ATP needed for growth. Understanding this metabolic landscape may provide strategies to overcome mechanisms of resistance to therapy in melanoma. AMP-activated protein kinase (AMPK) has been shown to inactivate BRAF by phosphorylating Ser 729, and in preclinical models, this can be used to enhance inhibitors of BRAFV600E. In the high ATP environment of a melanoma cell, AMPK is typically low but inducers of AMPK, such as biguanides, increase AMPK. The biguanide metformin does not enter melanoma cells efficiently due to the lack of organic cation transporter (OCT) expression on melanoma cells. However, phenformin does not require OCT for uptake. We are conducting a phase I trial in BRAF V600E-mutated melanoma patients using dabrafenib/trametinib and escalating doses of phenformin. One of the pharmacodynamic effects of phenformin is weight loss, which we are measuring. Interestingly, obesity has been associated with improved outcome in male melanoma patients treated with anti-PD1 antibodies. In contrast, our data in melanoma patients treated with anti-PD1 antibody immunotherapy do not show an association between outcome and obesity. Another consequence of anaerobic glycolysis is generation and excretion of large amounts of lactate. There is evidence that lactate can inhibit T-cell function, and we will discuss strategies to block lactate transport to enhance immunotherapy. Citation Format: Allison Betoff, Jonathan Zippin, Taha Merghoub, Paul B. Chapman, Jedd Wolchok. Targeting melanoma metabolism to overcome resistance to treatment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA10.