PDF(Pubmed)
Abstract：
Chronic lymphocytic leukemia (CLL) is common amongst leukemic malignancies, prompting dedicated investigation throughout the years. Over the last decade, the treatment for CLL has significantly advanced with agents targeting B-cell lymphoma 2 (BCL2), Bruton\'s tyrosine kinase, and CD20. Single agents or combinations of these targets have proven efficacy. Unfortunately, resistance to one or multiple of the new treatment targets develops. Our review investigates various mechanisms of resistance to BCL2 inhibitors, including mutations in BCL2, alterations in the Bcl protein pathway, epigenetic modifications, genetic heterogeneity, Richter transformation, and alterations in oxidative phosphorylation. Additionally, the review will discuss potential avenues to overcome this resistance with novel agents such as bispecific antibodies, Bruton\'s tyrosine kinase (BTK) degraders, non-covalent BTK inhibitors, and chimeric antigen receptor T (CART).
摘要：
慢性淋巴细胞白血病（CLL）在白血病恶性肿瘤中很常见，促使多年来进行专门的调查。在过去的十年里，针对B细胞淋巴瘤2（BCL2）的药物对CLL的治疗显着进展，布鲁顿酪氨酸激酶，CD20这些靶标的单一药剂或组合已证明功效。不幸的是,对一个或多个新的治疗靶标产生抗性。我们的综述调查了对BCL2抑制剂的各种耐药机制，包括BCL2的突变，Bcl蛋白通路的改变，表观遗传修饰,遗传异质性，Richter转型,和氧化磷酸化的改变。此外,这篇综述将讨论用双特异性抗体等新型药物克服这种耐药性的潜在途径，布鲁顿酪氨酸激酶（BTK）降解剂，非共价BTK抑制剂，和嵌合抗原受体T(CART)。
