mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma

SIMPLE SUMMARY: From a screen for metabolic inhibition by a panel of approved anticancer drugs and combining the lead compound with a mammalian target of rapamycin complex 1 (mTORC1) inhibitor, we demonstrated that the combination of ponatinib and sirolimus leads to synergistic tumor growth inhibition in a mouse xenograft tumor model of multiple myeloma. The rationale of combining the two drugs was to prevent metabolic escape due to glycolysis reprogramming and residual oxidative phosphorylation (OXPHOS). The robust increases in reactive oxygen species (ROS) due to a block in glycolysis were shown to be the lead contributor of cell viability loss. The drug combination in the doses used displayed no overt toxicity in the treated animals. ABSTRACT: Studies in targeting metabolism in cancer cells have shown the flexibility of cells in reprogramming their pathways away from a given metabolic block. Such behavior prompts a combination drug approach in targeting cancer metabolism, as a single compound may not address the tumor intractability. Overall, mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated as enabling metabolic escape in the case of a glycolysis block. From a library of compounds, the tyrosine kinase inhibitor ponatinib was screened to provide optimal reduction in metabolic activity in the production of adenosine triphosphate (ATP), pyruvate, and lactate for multiple myeloma cells; however, these cells displayed increasing levels of oxidative phosphorylation (OXPHOS), enabling them to continue generating ATP, although at a slower pace. The combination of ponatinib with the mTORC1 inhibitor, sirolimus, blocked OXPHOS; an effect also manifested in activity reductions for hexokinase 2 (HK2) and glucose-6-phosphate isomerase (GPI) glycolysis enzymes. There were also remarkably higher levels of reactive oxygen species (ROS) produced in mouse xenografts, on par with increased glycolytic block. The combination of ponatinib and sirolimus resulted in synergistic inhibition of tumor xenografts with no overt toxicity in treated mice for kidney and liver function or maintaining weight.