Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

SIMPLE SUMMARY: Proteostasis is a balance between protein formation and degradation. All cells maintain their proteome throughout their lifespan. Malignant cells rely on protein degradation mechanisms to replenish cellular supplies of amino acids. Interference with the protein degradation machinery has become an effective method of fighting hematological malignancies, i.e., using proteasome inhibitors in cases of multiple myeloma and other lymphomas. Newer modalities have emerged, including proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras (LYTAC), and other techniques for protein degradation that lead to cellular apoptosis. The current review focuses on targeted protein degradation and its use in the treatment of hematological malignancies. ABSTRACT: Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studies have led to the development of proteasome inhibitors, which have advanced into drugs (such as bortezomib) used in the treatment of certain hematological tumors, including multiple myeloma. New therapeutic options have been studied making use of the so-called proteolysis-targeting chimeras (PROTACs), that bind desired proteins with a linker that connects them to an E3 ubiquitin ligase, resulting in proteasomal-targeted degradation. This review examines the mechanisms of protein degradation in the cells of the hematopoietic system, explains the role of dysfunctional protein degradation in the pathogenesis of hematological malignancies, and discusses the current and future advances of therapies targeting these pathways, based on an extensive search of the articles and conference proceedings from 2005 to April 2022.