A research team led\nby Chuxia Deng, chair professor in the Faculty of Health Sciences (FHS) at the University\nof Macau (UM), has made a significant breakthrough in understanding resistance to\nradiotherapy. The study, for the\nfirst time, revealed distinct mechanisms underlying tumour-cell responses induced by\nlow-dose versus high-dose radiotherapy. <\/a>The team found that low-dose\nradiotherapy can significantly promote de novo protein synthesis and induce\nprotein damage. Moreover, when combined with proteasome inhibitors, protein-damage clearance can be effectively\nblocked, thereby enhancing anti-tumour efficacy while reducing\ntoxicity to normal tissues. The research findings have been published in the international journal Drug\nResistance Updates<\/i>.<\/p> Radiotherapy is a\ncornerstone of the treatment for solid\ntumours, with around half of all cancer patients receiving it. However, some patients are intrinsically resistant to radiotherapy, while others develop acquired resistance after treatment.\nTo reduce the toxic side effects of high-dose radiotherapy on normal tissues,\nclinical practice often uses fractionated low-dose radiotherapy. However, prolonging the\ntreatment period may promote resistance. Traditionally, resistance to radiotherapy has primarily been\nattributed to DNA damage repair mechanisms, while the role of protein damage\nhas long been overlooked.<\/p> By systematically\ncomparing the effects of low- and high-dose radiotherapy on tumour cells, the\nresearch team discovered that the cellular\nresponses differed markedly.\nHigh-dose radiotherapy triggers strong responses to DNA damage, activates cell-cycle checkpoints, causes cell-cycle arrest,\nsuppresses proliferation, and inhibits de novo protein synthesis. In contrast,\nlow-dose radiotherapy causes weaker DNA damage. While cell-cycle\nprogression is largely maintained, de novo protein synthesis is significantly\npromoted, including a large number of DNA repair-related proteins.<\/p> Further studies have revealed that protein\ndamage induced by radiotherapy mainly affects\nnewly synthesised proteins, and that\nthe severity of this damage is closely correlated with the rate of protein synthesis. Blocking protein synthesis can\ncompletely prevent this type of damage, whereas promoting prematurely\nterminated nascent peptide chains can\nexacerbate it. In dividing cells, where protein synthesis is\nmore active, radiotherapy-induced protein damage is even more pronounced.<\/p> Since low-dose\nradiotherapy significantly promotes de novo protein synthesis, resulting\nin efficient protein damage comparable\nto that caused by high-dose radiotherapy, the research team proposed targeting protein damage clearance as\na novel combination therapy.\nExperiments showed that combining low-dose radiotherapy with proteasome inhibitors\nprevents the clearance of damaged\nproteins, leading to their substantial accumulation. At the same time, this combination\nsignificantly suppresses de novo protein synthesis, thereby preventing the\nproduction of key DNA repair proteins, weakening DNA repair capacity, and markedly increasing\ntumour-cell death.<\/p> In animal models, low-dose\nradiotherapy combined with proteasome inhibitors was as effective as high-dose radiotherapy combined with\nthe same strategy, but with significantly less toxicity to normal tissues. In the high-dose group, clear skin toxicity\nwas observed; in contrast, the low-dose combination group showed no significant\nadverse effects. The combined\nstrategy also demonstrated superior anti-tumour effects compared with radiotherapy alone in three-dimensional tumour tissue slices and patient-derived organoid\nmodels.<\/p> Notably, this protein damage response\nmechanism is similar to the team\u2019s earlier\nresearch on chemotherapy resistance. Multiple chemotherapeutic drugs preferentially bind\nto newly synthesised proteins, causing misfolding and oxidative damage. Cancer\ncells then survive through a \u2018protein damage response\u2019, which includes ubiquitination-mediated\ntagging and proteasome clearance. The study further confirmed that proteasome\ninhibitors available for clinical use can effectively reverse this form of resistance. This research was published in the\ninternational journal Cell Discovery<\/i>.<\/p> Overall, this study\nis the first to systematically elucidate differences in cellular responses to\nradiotherapy at different doses and proposes a new strategy that combines low-dose radiotherapy\nwith proteasome inhibitors. This approach maintains anti-tumour efficacy while\nsubstantially reducing toxicity, offering\nvaluable insights for optimising radiotherapy in clinical settings.<\/p> The corresponding\nauthors of this study are Prof Deng and Adjunct Associate Professor Xu Xiaoling in FHS. The first authors\nare Research Assistant Professor Shao Fangyuan, and PhD student Li Zongjie in FHS. Other FHS members also made substantial\ncontributions to the study, including Professor Edwin Cheung Chong Wing, Associate Professor Tam Kin Yip, and PhD students Ran Maoxin, Chen Yujun, Liu Junlin, Li Bo, Hong Mengyu, Si Qi, Ye Xiangyang, Chu Xiangpeng, and Hou Yuxing. The research was funded by the Natural\nScience Foundation of China (Grant Nos.: 82573786, 82030094 and 82303921), the National\nKey R&D Program (Grant No.: 2021YFE0206300), the Science and Technology\nDevelopment Fund of the Macao SAR (Grant Nos.: 0009\/2022\/AKP,\n0138\/2022\/A, 0071\/2023\/RIA2, 0054\/2023\/RIA1, 0129\/2024\/RIA2, 0059\/2024\/ITP2, 0064\/2025\/ITP1), and the\nUniversity of Macau (Grant Nos.: CPG2024-00020-FHS,\nCPG2025-00035-FHS, MYRG2023-00029-FHS). The full version of the research article can be accessed at: https:\/\/pubmed.ncbi.nlm.nih.gov\/41844504\/<\/a><\/p> <\/p>