在现代慢性淋巴细胞白血病 (CLL) 靶向治疗中，由于遗传异常而导致的 p53 功能丧失仍然是一个重大挑战。这是因为，即使是目前 CLL 治疗的主要治疗手段的靶向药物，也不能直接靶向 p53 或恢复其被破坏的途径。因此，这些 p53 相关异常常常伴随着对治疗的抵抗和不利的临床结果。未来临床研究的一个基本目标应该是解决表面上“不可成药”的 p53 通路。目前，正在探索多种治疗方法来解决 TP53 功能障碍并改善高危 CLL 的预后。这些方法包括使用癌蛋白鼠双分钟 2 抑制剂、小分子 p53 重激活剂、输出蛋白 1 (XPO1) 抑制剂以及共济失调毛细血管扩张突变和 Rad3 相关 (ATR) 抑制剂。这些 p53 靶向策略的组合，以及 B 细胞受体或 B 细胞淋巴瘤 2 (BCL-2) 抑制剂等已确立的新型疗法，可能会塑造这种具有挑战性的疾病的治疗试验的未来。© 2023 约翰·威利

In the modern era of Chronic Lymphocytic Leukemia (CLL) targeted therapy, the loss of p53 function due to genetic abnormalities remains a significant challenge. This is because even targeted agents, which are currently the mainstay of treatment for CLL, do not directly target p53 or restore its disrupted pathway. Consequently, resistance to therapy and unfavorable clinical outcomes often accompany these p53-related abnormalities. An essential goal of future clinical research should be to address the ostensibly "undruggable" p53 pathway. Currently, multiple therapeutic approaches are being explored to tackle TP53 dysfunction and improve outcomes in high-risk CLL. These approaches include the use of oncoprotein murine double minute 2 inhibitors, small-molecule p53 reactivators, exportin 1 (XPO1) inhibitors, and ataxia-telangiectasia mutated and Rad3-related (ATR) inhibitors. Combinations of these p53-targeting strategies, along with established novel therapies such as B-cell receptor or B-cell lymphoma-2 (BCL-2) inhibitors, may shape the future of therapeutic trials in this challenging-to-treat disease.© 2023 John Wiley & Sons Ltd.