Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers

SIMPLE SUMMARY: The development of BCL-2 inhibitors as a pivotal approach in cancer treatment lies in their ability to effectively trigger apoptosis in tumor cells. Venetoclax, a highly selective BCL-2 inhibitor, has exhibited robust antitumor capacity in hematologic malignancies. However, patients undergoing venetoclax treatment often develop drug resistance, leading to a reduced sensitivity to BCL-2 inhibition therapy. Given the pronounced variations in venetoclax effectiveness attributed to patient heterogeneity, we demonstrated crucial gene mutations for the accurate prediction of the clinical responses to venetoclax. Our review encompasses not only advancements in hematologic tumors but also a comprehensive overview of recent progress in employing BCL-2 inhibitors to treat solid tumors. We summarize predictive biomarkers and synergistic drug combinations aimed at enhancing the efficacy of BCL-2 inhibition in solid tumors. This review offers innovative perspectives for translational studies on the application of BCL-2 inhibitors in cancer therapy. ABSTRACT: 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.