Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need. Clinical and preclinical studies have been conducted to identify factors driving resistance. Among them, the most documented are molecular alterations includingIDH,FLT3,TP53, and the newly describedBAXmutations. Several non-genetic factors are also described such as metabolic plasticity, changes in anti-apoptotic protein expression, and dependencies, as well as monocytic differentiation status. Strategies to overcome venetoclax resistance are being developed in clinical trials, including triplet therapies with targeted agents targeting IDH, FLT3, as well as the recently developed menin inhibitors or immunotherapies such as antibody–drug conjugated or monoclonal antibodies. A better understanding of the molecular factors driving venetoclax resistance by single-cell analyses will help the discovery of new therapeutic strategies in the future.
维奈克拉是一种BH3模拟剂，通过与抗凋亡蛋白BCL2相互作用，促进线粒体释放细胞色素c，进而激活半胱天冬酶并诱导细胞死亡。维奈克拉联合阿扎胞苷（VEN-AZA）已成为不适合强化化疗的急性髓系白血病患者的新标准治疗方案。在III期VIALE-A研究中，VEN-AZA方案显示出65%的总缓解率和14.7个月的总生存期，而阿扎胞苷单药对照组分别为22%和8个月。尽管这些结果令人鼓舞，但维奈克拉的复发和原发性耐药仍频繁发生，成为尚未满足的临床需求。目前已有临床和临床前研究致力于识别导致耐药的因素，其中证据最充分的是分子学改变，包括IDH、FLT3、TP53以及新近报道的BAX突变。此外还发现多种非遗传因素，如代谢可塑性、抗凋亡蛋白表达与功能依赖性的改变，以及单核细胞分化状态。针对克服维奈克拉耐药的策略正在临床试验中开发，包括联合IDH或FLT3靶向药物的三联疗法、新近研发的menin抑制剂，以及抗体-药物偶联物或单克隆抗体等免疫疗法。通过单细胞分析技术更深入地理解驱动维奈克拉耐药的分子机制，将有助于未来开发新的治疗策略。
肿瘤(癌症)患者之家