Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects.
靶向由B细胞淋巴瘤-2（BCL-2）抗凋亡蛋白调控的内源性凋亡通路，能够克服癌细胞对凋亡的逃避。BCL-2抑制剂通过诱导肿瘤细胞凋亡，已发展成为治疗癌症的重要手段。作为目前研究最广泛的BCL-2抑制剂，维奈克拉对BCL-2具有高度选择性，能有效抑制肿瘤存活。其问世与发展显著改变了血液系统恶性肿瘤的治疗格局，尤其在慢性淋巴细胞白血病和急性髓系白血病中，已被明确纳入推荐治疗方案。此外，维奈克拉联合其他药物在复发难治性多发性骨髓瘤及部分淋巴瘤中也展现出显著疗效。尽管维奈克拉在临床前实验和临床试验中表现出突出的抗肿瘤作用，但在真实世界患者群体中仍存在较大的疗效个体差异，药物敏感性下降将导致疾病复发或进展。不同分子特征患者的治疗效果可能存在显著差异，关键基因突变可能导致对维奈克拉的敏感性不同。需要鉴定和验证更多新型生物标志物，以准确预测BCL-2抑制疗法的有效性。此外，本文综述了BCL-2抑制剂在实体瘤治疗中的最新研究进展，表明大量临床前模型通过联合治疗显示出良好前景。维奈克拉在实体瘤中的应用值得进一步临床研究以明确其发展前景。
Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers
肿瘤(癌症)患者之家