Optimization of Autophagy Inhibition as a Clinical Target for Brain Tumors
Technical Report,01 Aug 2018,31 Jul 2019
University of Colorado Aurora United States
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Autophagy is a multi-stage process. Drugs targeting both early initiation and late fusion stages of this process are available. The specific stage of autophagy targeted may influence cancer treatment outcomes. CNS tumors with the BRAFV600E mutation are autophagy dependent, and late stage autophagy inhibition improves response to targeted BRAF inhibitors BRAFi. We investigated early stage inhibition for autophagy dependent CNS tumors. BRAFi-sensitive and resistant AM38 and MAF794cell lines were evaluated for response to pharmacologic and genetic inhibition of ULK1 and VPS34, two crucial subunits of the autophagy initiation complexes. Changes in autophagy were monitored by western blot and flow cytometry. Short and long-term assays were evaluated. Tumor cells exhibited reduced autophagic flux with pharmacologic and genetic inhibition of ULK1or VPS34. Pharmacologic inhibition reduced cell survival in a dose dependent manner for both targets. Genetic inhibition reduced cell survival and confirmed it was an autophagy specific effect. Pharmacologic and genetic inhibition were also synergistic with BRAFi, irrespective of RAFi sensitivity. Inhibition of ULK1 and VPS34 are potentially viable clinical targets in autophagy dependent CNS tumors. Further evaluation is needed to determine if early and late stage autophagy inhibition are equally efficacious to determine the optimal clinical target for patients.
- Medicine and Medical Research