ENGINEERING CELL DEATH PATHWAYS FOR CANCER THERAPY: EMERGING CONCEPTS IN APOPTOSIS AND AUTOPHAGY

Abstract

Cancer is characterised by resistance to programmed cell death, and of the various known cell death mechanisms, apoptosis and autophagy continue to be the most well characterised and treatable. The molecular architecture of the intrinsic and extrinsic apoptotic pathways, the fundamental autophagy mechanism, and the complex communication network focused on mTOR signalling, BCL-2/Beclin-1 and p53 interactions that determine whether a stressed cell survives or dies are summarised in this review. We look at different methodologies for “engineering” pathways such as BH3 mimetics, epigenetic modulators, CRISPR/Cas9 and RNA interference-based gene editing and delivery systems which enabled by nanotechnology which is enabled the accurate, tumor-selective death induction. We also discuss the integration with synthetic lethality, immunotherapy, and artificial intelligence-driven drug discovery to tackle the specific characteristics of autophagy. Therapeutic agents such as venetoclax, temsirolimus, hydroxychloroquine, and everolimus are examples of potential therapeutic approaches but also have some drawbacks like resistance, delivery, and heterogeneity. Perhaps, we concluded that combination therapeutic approaches, which are biomarker-guided, multi-target, and locally targeted as compared to single pathway modalities, are the future of programmed cell death engineering.