Targeting MCL-1 protein to treat cancer: opportunities and challenges

Frontiers in Oncology

Oncology

Shady I. Tantawy¹  Natalia Timofeeva¹  Aloke Sarkar¹  Varsha Gandhi² 

[1]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

[2]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

[3]Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

关键词: MCL-1 protein;    BCL-2 family proteins;    MCL-1 inhibitors;    apoptosis;    BCL-2 family;    cancer therapy;   

DOI  :  10.3389/fonc.2023.1226289

 received in 2023-05-24, accepted in 2023-07-03,  发布年份 2023

来源: Frontiers

【 摘 要 】

Evading apoptosis has been linked to tumor development and chemoresistance. One mechanism for this evasion is the overexpression of prosurvival B-cell lymphoma-2 (BCL-2) family proteins, which gives cancer cells a survival advantage. Mcl-1, a member of the BCL-2 family, is among the most frequently amplified genes in cancer. Targeting myeloid cell leukemia-1 (MCL-1) protein is a successful strategy to induce apoptosis and overcome tumor resistance to chemotherapy and targeted therapy. Various strategies to inhibit the antiapoptotic activity of MCL-1 protein, including transcription, translation, and the degradation of MCL-1 protein, have been tested. Neutralizing MCL-1’s function by targeting its interactions with other proteins via BCL-2 interacting mediator (BIM)S2A has been shown to be an equally effective approach. Encouraged by the design of venetoclax and its efficacy in chronic lymphocytic leukemia, scientists have developed other BCL-2 homology (BH3) mimetics—particularly MCL-1 inhibitors (MCL-1i)—that are currently in clinical trials for various cancers. While extensive reviews of MCL-1i are available, critical analyses focusing on the challenges of MCL-1i and their optimization are lacking. In this review, we discuss the current knowledge regarding clinically relevant MCL-1i and focus on predictive biomarkers of response, mechanisms of resistance, major issues associated with use of MCL-1i, and the future use of and maximization of the benefits from these agents.

【 授权许可】

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Copyright © 2023 Tantawy, Timofeeva, Sarkar and Gandhi