肿瘤细胞治疗研究
英文原题：Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.
Bruton酪氨酸激酶抑制剂（BTKis）自问世以来，显著改善了B细胞恶性肿瘤的治疗格局，包括慢性淋巴细胞白血病、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤和Waldenstr m巨球蛋白血症。
自十年前first-in-class BTKi ibrutinib问世以来，Bruton tyrosine kinase inhibitors (BTKis) 显著改善了B细胞恶性肿瘤的治疗格局，包括慢性淋巴细胞白血病、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤和Waldenstr m巨球蛋白血症。尽管在临床上取得了成功，但BTKis耐药的出现构成了重大的治疗挑战。耐药机制是多因素的，包括基因突变、替代性致癌信号通路的激活、蛋白表达失调、肿瘤微环境的改变以及代谢重编程。为应对这些挑战，多种治疗策略正在积极研究中，例如下一代非共价BTKis、靶向BTK的蛋白水解方法（如PROTACs）以及旨在绕过或克服耐药通路的联合治疗（如与双特异性抗体或CAR-T [CAR T] 细胞联合）。本综述全面概述了驱动BTKi耐药的机制，并讨论了当前旨在改善B细胞恶性肿瘤治疗结局的临床前和临床策略。
Bruton tyrosine kinase inhibitors (BTKis) have markedly improved the treatment landscape for B cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and Waldenstr m's macroglobulinemia, since the introduction of the first-in-class BTKi, ibrutinib, a decade ago. Despite their clinical success, the emergence of resistance to BTKis poses a significant therapeutic challenge. The mechanisms of resistance are multifactorial and include genetic mutations, activation of alternative oncogenic signaling pathways, dysregulated protein expression, alterations in the tumor microenvironment, and metabolic reprogramming. To address these challenges, several therapeutic strategies are under active investigation, such as next-generation noncovalent BTKis, BTK-targeting proteolysis approaches (e.g., PROTACs), and combination therapies (e.g., with bispecific antibodies or chimeric antigen receptor T [CAR T] cells) designed to bypass or overcome resistance pathways. This review provides a comprehensive overview of the mechanisms driving BTKi resistance and discusses current preclinical and clinical strategies aimed at improving therapeutic outcomes in B cell malignancies.
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