Abstract
Autophagy is a multistage process. Progress within the field has led to the development of agents targeting both early (initiation) and late (fusion) stages of this process. The specific stage of autophagy targeted may influence cancer treatment outcomes. We have previously shown that central nervous system (CNS) tumors with the BRAFV600E mutation are autophagy dependent, and late-stage autophagy inhibition improves the response to targeted BRAF inhibitors (BRAFi) in sensitive and resistant cells. Drugs directed toward initiation of autophagy have been shown to reduce tumor cell death in some cancers, but have not been assessed in CNS tumors. We investigated early-stage inhibition for autophagy-dependent CNS tumors. BRAFi-sensitive and resistant AM38 and MAF794 cell lines were evaluated for the 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. Survival was evaluated in short- and long-term growth assays. Tumor cells exhibited a reduced autophagic flux with pharmacologic and genetic inhibition of ULK1 or VPS34. Pharmacologic inhibition reduced cell survival in a dose-dependent manner for both targets. Genetic inhibition reduced cell survival and confirmed that 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-stage autophagy inhibition is equal to late-stage inhibition to determine the optimal clinical target for patients.
Highlights
Macroautophagy plays a critical role in maintaining cellular homeostasis by eliminating damaged organelles and misfolded proteins
Recent studies support the idea of autophagy facilitating cancer cell survival and resistance to chemotherapeutic drugs
Recognition and diagnosis of central nervous system (CNS) tumors with BRAFV600E mutations are increasing with the expanded availability of tumor genetic analysis, in subsets of CNS tumors including gangliogliomas, pleomorphic xanthoastrocytomas, and epithelioid glioblastomas[34,35]
Summary
Macroautophagy (referred to hereafter as autophagy) plays a critical role in maintaining cellular homeostasis by eliminating damaged organelles and misfolded proteins. It functions through a multistage degradation process which can be organized into five distinct phases: initiation, elongation, closure, maturation, and degradation[1,2]. Initiation, the first step of autophagy, begins with the cell’s activation of the Unc51-like kinase 1 (ULK1) complex which signals the cell to begin formation of the Autophagy’s role in the pathogenesis of human diseases appears contextual with responses varying by disease type[5]. The exact processes by which autophagy can assume either of these roles remain under investigation. One overriding theory is that catabolism acting through autophagy leads to cell survival, Official journal of the Cell Death Differentiation Association
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