Targeted Protein Degradation in Cancer: From PROTACs to Lysosome-Based Strategies

The ability to target “undruggable” oncoproteins is shifting the paradigm of cancer drug discovery from simple inhibition (occupancy-driven) to total degradation (event-driven). While traditional small molecule inhibitors have been the cornerstone of oncology, they are often limited by the need for high affinity and the inability to target proteins lacking distinct active sites. Targeted Protein Degradation (TPD) has emerged as a revolutionary approach to overcome these limitations.Much of the initial success in TPD has focused on the Ubiquitin-Proteasome System (UPS), utilizing Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues to eliminate intracellular oncogenic proteins. However, the field is rapidly expanding beyond the proteasome.To address membrane-bound and extracellular proteins—targets previously inaccessible to PROTACs—novel strategies harnessing the lysosomal degradation pathways are now at the forefront of pharmacological research. Technologies such as Lysosome-Targeting Chimeras (LYTACs), Autophagy-Targeting Chimeras (AUTACs), and ATTECs are opening new frontiers in degrading cell-surface receptors, aggregated proteins, and secreted factors.This Research Topic aims to cover the full spectrum of TPD in oncology, bridging the gap between proteasome-mediated and lysosome-mediated degradation. We invite submissions that explore the pharmacology, design, and clinical translation of these modalities.We particularly welcome contributions covering: Proteasome-Mediated Degradation: Design and optimization of PROTACs and -Molecular Glues for novel intracellular cancer targets. Lysosome-Based Degradation: Development and mechanism of action of LYTACs, AUTACs, and other lysosome- or autophagy-mediated degraders for membrane and extracellular targets (e.g., EGFR, PD-L1). Pharmacology and DMPK: Understanding the unique pharmacokinetic properties, bioavailability, and tissue distribution of TPD agents. Mechanisms of Resistance: Investigating how cancer cells develop resistance to degraders (e.g., machinery downregulation) and strategies to overcome it. Combination Therapies: Synergistic effects of combining TPD agents with immunotherapies or standard chemotherapeutics. Rational Drug Design: Structural biology and computational approaches to improve linker stability and E3 ligase/lysosome receptor selection.By integrating advances in both ubiquitin-proteasome and lysosomal pathways, this collection aims to provide a comprehensive view of the next generation of anti-cancer therapeutics. Topic editors: Ilaria BASILE, Huabing Sun, Pablo Morentin Gutierrez Source: https://www.frontiersin.org/research-topics/83459/targeted-protein-degradation-in-cancer-from-protacs-to-lysosome-based-strategies