Targeting MCL-1 protein to treat cancer: opportunities and challenges
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1226289/full |
| _version_ | 1827877820132491264 |
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| author | Shady I. Tantawy Natalia Timofeeva Aloke Sarkar Varsha Gandhi Varsha Gandhi |
| author_facet | Shady I. Tantawy Natalia Timofeeva Aloke Sarkar Varsha Gandhi Varsha Gandhi |
| author_sort | Shady I. Tantawy |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T17:42:51Z |
| format | Article |
| id | doaj.art-99a0f4ba783c49fe9111b80f5dcc04c6 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-12T17:42:51Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-99a0f4ba783c49fe9111b80f5dcc04c62023-08-04T03:02:28ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-07-011310.3389/fonc.2023.12262891226289Targeting MCL-1 protein to treat cancer: opportunities and challengesShady I. Tantawy0Natalia Timofeeva1Aloke Sarkar2Varsha Gandhi3Varsha Gandhi4Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesEvading 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.https://www.frontiersin.org/articles/10.3389/fonc.2023.1226289/fullMCL-1 proteinBCL-2 family proteinsMCL-1 inhibitorsapoptosisBCL-2 familycancer therapy |
| spellingShingle | Shady I. Tantawy Natalia Timofeeva Aloke Sarkar Varsha Gandhi Varsha Gandhi Targeting MCL-1 protein to treat cancer: opportunities and challenges Frontiers in Oncology MCL-1 protein BCL-2 family proteins MCL-1 inhibitors apoptosis BCL-2 family cancer therapy |
| title | Targeting MCL-1 protein to treat cancer: opportunities and challenges |
| title_full | Targeting MCL-1 protein to treat cancer: opportunities and challenges |
| title_fullStr | Targeting MCL-1 protein to treat cancer: opportunities and challenges |
| title_full_unstemmed | Targeting MCL-1 protein to treat cancer: opportunities and challenges |
| title_short | Targeting MCL-1 protein to treat cancer: opportunities and challenges |
| title_sort | targeting mcl 1 protein to treat cancer opportunities and challenges |
| topic | MCL-1 protein BCL-2 family proteins MCL-1 inhibitors apoptosis BCL-2 family cancer therapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1226289/full |
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