Torices Leire, Nunes-Xavier Caroline E, Pulido Rafael
Biobizkaia Health Research Institute, Barakaldo, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBERER, ISCIII, Spain.
IUBMB Life. 2025 May;77(5):e70018. doi: 10.1002/iub.70018.
Tumor suppressor genes are frequently targeted by mutations introducing premature termination codons (PTC) in the protein coding sequence, both in sporadic cancers and in the germline of patients with cancer predisposition syndromes. These mutations have a high pathogenic impact since they generate C-terminal truncated proteins with altered stability and function. In addition, PTC mutations trigger transcript degradation by nonsense-mediated mRNA decay. Suppression of PTC by translational readthrough restores protein biosynthesis and stabilizes the PTC-targeted mRNA, making a suitable therapeutic approach the reconstitution of active full-length tumor suppressor proteins by pharmacologically-induced translational readthrough. Here, we review the recent advances in small molecule pharmacological induction of translational readthrough of disease-associated PTC from tumor suppressor genes, and discuss the therapeutic potential of translational readthrough in specific groups of patients with hereditary syndromic cancers.
肿瘤抑制基因在散发性癌症以及癌症易感综合征患者的种系中，经常因蛋白质编码序列中引入过早终止密码子（PTC）的突变而成为靶点。这些突变具有很高的致病影响，因为它们会产生稳定性和功能改变的C末端截短蛋白。此外，PTC突变会通过无义介导的mRNA降解触发转录本降解。通过翻译通读抑制PTC可恢复蛋白质生物合成并稳定PTC靶向的mRNA，从而使通过药理学诱导的翻译通读来重建活性全长肿瘤抑制蛋白成为一种合适的治疗方法。在此，我们综述了小分子药物诱导肿瘤抑制基因疾病相关PTC翻译通读的最新进展，并讨论了翻译通读在特定遗传性综合征癌症患者群体中的治疗潜力。
