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

Author:

Xu Jiaxuan1,Dong Xiaoqing1,Huang David C. S.23,Xu Peipei1,Zhao Quan1ORCID,Chen Bing1ORCID

Affiliation:

1. Department of Hematology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210008, China

2. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia

3. Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia

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.

Funder

National Natural Science Foundation of China

Key Research Project of Jiangsu Provincial Health Commission

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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