Targeting autophagy in cancer

Abstract

Macroautophagy (known as autophagy) is a highly regulated multi-step process that is involved in the bulk degradation of cellular proteins and organelles to provide macromolecular precursors that are recycled or that are used to fuel metabolic pathways. Autophagy can be targeted for both stimulation and inhibition. Stimulation can be achieved through cellular stress (nutrient deprivation) and mTOR inhibition, and inhibition can be achieved through multiple targets both upstream (ULK1, Beclin 1 and VPS34 inhibitors) and downstream of the site of lysosomal fusion with the autophagosome. Early clinical trials have demonstrated the feasibility and potential benefit of clinically inhibiting autophagy in multiple cancer types, including glioblastoma, pancreatic cancer, melanoma, sarcoma and multiple myeloma. Ongoing studies are developing novel clinical biomarkers that can be used to monitor autophagy in patients, including electron microscopy evaluation of autophagosome number in peripheral blood mononuclear cells and tumour samples, LC3II and ATG13 puncta by immunohistochemistry, and novel imaging techniques that use positron emission tomography and metabolomics profiles. The role of autophagy in regulating tumour immune responses is unclear, with arguments both for and against autophagy inhibition. Further research is needed to define the safety and utility of autophagy inhibition while also maximizing tumour immune responses for improved clinical outcomes. Markers of autophagy dependence have the potential to identify patients who will best respond to autophagy inhibition therapy. Such markers include altered RAS signalling, BRAF mutations, signal transducer and activator of transcription 3 (STAT3) activation, autophagy-dependent secretion of interleukins and p53 status. Autophagy can be an effective cancer escape mechanism and has been implicated in the development of resistance in multiple cancer types, including BRAF-mutated central nervous system (CNS) tumours and melanoma, non-small-cell lung cancer (NSCLC), bladder cancer and thyroid cancer. Combination therapy with autophagy inhibition in these cancers has the potential to reduce and reverse resistance to therapy.