Abstract
As a dynamic regulator for short-lived protein degradation and turnover, the ubiquitin-proteasome system (UPS) plays important roles in various biological processes, including response to cellular stress, regulation of cell cycle progression, and carcinogenesis. Over the past decade, research on targeting the cullin-RING (really interesting new gene) E3 ligases (CRLs) in the UPS has gained great momentum with the entry of late-phase clinical trials of its novel inhibitors MLN4924 (pevonedistat) and TAS4464. Several preclinical studies have demonstrated the efficacy of MLN4924 as a radiosensitizer, mainly due to its unique cytotoxic properties, including induction of DNA damage response, cell cycle checkpoints dysregulation, and inhibition of NF-κB and mTOR pathways. Recently, the PROteolysis TArgeting Chimeras (PROTACs) technology was developed to recruit the target proteins for CRL-mediated polyubiquitination, overcoming the resistance that develops inevitably with traditional targeted therapies. First-in-class cell-permeable PROTACs against critical radioresistance conferring proteins, including the epidermal growth factor receptor (EGFR), androgen receptor (AR) and estrogen receptor (ER), cyclin-dependent kinases (CDKs), MAP kinase kinase 1 (MEK1), and MEK2, have emerged in the past 5 years. In this review article, we will summarize the most important research findings of targeting CRLs for radiosensitization.
Highlights
Over 60% of cancer patients undergo radiotherapy (RT) during their course of illness, with an estimated 40% contribution toward curative cancer treatment [1, 2]
Driven by the fact that the development of radioresistance is largely determined by factors such as DNA damage response DDR activation after ionizing radiation (IR), cell cycle checkpoints controls, and anti-apoptotic pathways dysregulation, it is essential to investigate the potential of using NEDDylation inhibitors as radiosensitizers [64]
Pharmacological intervention of protein turnover offers a new therapeutic window for radiosensitization. Driven by their unique cytotoxic mechanisms, the novel strategies targeting the ubiquitin-proteasome system (UPS) with NEDDylation inhibitors and the PROteolysis TArgeting Chimeras (PROTACs) carry great potential as radiosensitizers to improve the efficacy of RT
Summary
Over 60% of cancer patients undergo radiotherapy (RT) during their course of illness, with an estimated 40% contribution toward curative cancer treatment [1, 2]. Targeting CRL for Radiosensitization suggested increased efficacy and improved survival rates of these new strategies, highlighting the clinical importance of using targeted agents as radiosensitizers [4]. In the past decade, targeting the activities of cullin-RING (really interesting new gene) E3 ligases (CRLs) in the ubiquitinproteasome system (UPS) has gained considerable momentum for cancer treatment with the entry of several late-phase clinical trials of its first-in-class inhibitor MLN4924 (pevonedistat) [9]. The revised hypothesis describes the scenario whereby combined-modality of targeted therapies and RT can improve the therapeutic outcomes by five mechanisms: [1] spatial cooperation, [2] temporal modulation, [3] biological cooperation, [4] cytotoxic enhancement, and [5] normal tissue protection [4]
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