TY - JOUR
T1 - Targeting MCL-1 protein to treat cancer
T2 - opportunities and challenges
AU - Tantawy, Shady I.
AU - Timofeeva, Natalia
AU - Sarkar, Aloke
AU - Gandhi, Varsha
N1 - Funding Information:
Author VG has received research grants from Pharmacyclics, Acerta, Gilead, Sunesis, ClearCreek Bio, Infinity, and Loxo Oncology.
Funding Information:
This work was supported by a CLL Global Research Foundation Alliance and The University of Texas MD Anderson Cancer Center’s Moon Shot Program. Acknowledgments
Publisher Copyright:
Copyright © 2023 Tantawy, Timofeeva, Sarkar and Gandhi.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - apoptosis
KW - BCL-2 family
KW - BCL-2 family proteins
KW - cancer therapy
KW - MCL-1 inhibitors
KW - MCL-1 protein
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U2 - 10.3389/fonc.2023.1226289
DO - 10.3389/fonc.2023.1226289
M3 - Review article
C2 - 37601693
AN - SCOPUS:85168326926
SN - 2234-943X
VL - 13
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1226289
ER -