Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
IUBMB Life. 2024 Jan;76(1):4-25. doi: 10.1002/iub.2773. Epub 2023 Aug 25.
Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose-limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.
系统治疗在治疗转移性恶性肿瘤和液体肿瘤中至关重要。然而，患者对治疗的反应和耐受性通常较差，那些进入缓解期的患者往往会因难治性疾病而复发。联合治疗提供了一种克服化疗耐药机制和解决剂量限制毒性的方法。在分子水平上对肿瘤发生过程的深入了解使靶向治疗方法成为癌症研究的前沿，并且新型癌症生物标志物正在快速被识别，其中一些显示出潜在的治疗益处。核输入蛋白家族是可溶性受体，可介导蛋白质和 RNA 的核质穿梭，最近，核转运受体已被认为是新型抗癌靶点。针对核输出的抑制剂已被批准用于某些癌症类型的临床应用，而针对核输入的抑制剂则处于临床前研究阶段。从机制上讲，靶向核质穿梭已被证明可以通过将相关蛋白质和 mRNAs 核隔离来阻断致癌信号并恢复肿瘤抑制功能。因此，核转运抑制剂具有广谱抗癌活性，并具有与广泛的细胞毒性药物和其他靶向药物协同作用的潜力。本综述重点介绍了癌症中研究最多的核转运受体，即 XPO1 和 KPNB1，并强调了针对这些受体的抑制剂如何增强标准治疗和新型靶向药物联合治疗的治疗效果。此外，还提供了对研究较少的核输入蛋白的治疗靶向的更新综述，并讨论了对临床批准的核输出抑制剂的耐药性。
