Targeted protein degraders from an oncologist point of view: The Holy Grail of cancer therapy?. (January 2022)

• Record Type: Journal Article
• Authors: Ambrosini, Margherita; Fucà, Giovanni; Duca, Matteo; Damian, Silvia; De Santis, Francesca; Corti, Francesca; Cresta, Sara; de Braud, Filippo; Di Nicola, Massimo
• Is Part Of: Critical reviews in oncology/hematology. Volume 169(2022)
• Publication Date: 2022-01
• Subjects: Protein degradation -- PROTAC -- SNIPER -- Targeted therapy -- Cancer; Oncology -- Periodicals; Hematology -- Periodicals; 616.994
• DOI: 10.1016/j.critrevonc.2021.103532
• Languages: English
• ISSNs: 1040-8428

Abstract

Graphical abstract: Highlights: Protein degraders selectively degrade and deplete specific intracellular proteins. Protein degraders represent a promising strategy to enable the targeting of so far elusive cancer drivers. Protein degraders may prevent/overcome resistance to other targeted agents. The safety and target specificity are open issues in the clinical development of protein degraders. Abstract: In the era of precision medicine, monoclonal antibodies and small molecule inhibitors are the mainstays of the biological therapy in patients with solid tumors. However, resistance to treatment and the "undruggability" of certain key oncogenic proteins emerged as major limitations and jeopardize the clinical benefit of modern therapeutic approaches. Targeted protein degraders are novel molecules entering the early phase of clinical development that exploit the intracellular ubiquitine-proteasome system to promote a specific degradation of target proteins. Since the peculiar mechanism of action, targeted protein degraders have the potential to limit and overcome resistance to treatment and to allow a full actionability of certain cancer drivers that are actually elusive targets. Here, we discuss the state-of-the-art and the open issues in the development of these emerging biological agents from a clinical perspective and with a focus on solid tumors.