Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN -amplified neuroblastoma.

摘要: MYCN-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding both compensatory pathways and intrinsic redundancy cell systems exists implies use combination therapies effective durable responses necessary. Additionally, most targeted exploit an "Achilles' heel" tailored to genetics cancer under study. We performed unbiased screen on select therapy combinations correlated sensitivity with over 20 subsets found hypersensitive inhibitor lactate transporter MCT1, AZD3965, complex I mitochondrion, phenformin. Our data demonstrate MCT4 highly resistance lowly expressed neuroblastoma. Low combines high expression MCT2 MCT1 chaperone CD147 neuroblastoma, altogether conferring AZD3965 phenformin combination. result simultaneous disruption glycolysis oxidative phosphorylation, resulting dramatic adenosine triphosphate (ATP) production, endoplasmic reticulum stress, death. In mouse models was tolerable at concentrations where it shrank tumors did not increase white-blood-cell toxicity compared single drugs. Therefore, we can identify vulnerabilities put forth demonstrates efficacy tolerability vivo.