Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

• Autor(a) principal: Leonardo-Sousa, Carlota
• Data de Publicação: 2022
• Outros Autores: Carvalho, Andreia Neves, Guedes, Romina A., Fernandes, Pedro M. P., Aniceto, Natália, Salvador, Jorge A. R., Gama, Maria João, Guedes, Rita C.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/103390; https://doi.org/10.3390/molecules27072201
• topic: ubiquitin–proteasome pathway; proteasome inhibitors; mechanisms of resistance; innate resistance; acquired resistance; multiple myeloma; cancer; Adult; Bortezomib; Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Quality of Life; Antineoplastic Agents; Multiple Myeloma; Neoplasms

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity-a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.