Abstract
Apoptosis is critical for embryonic development, tissue homeostasis, and the removal of infected or otherwise dangerous cells. It is controlled by three subgroups of the BCL-2 protein family—the BH3-only proteins that initiate cell death; the effectors of cell killing, BAX and BAK; and the antiapoptotic guardians, including MCL-1 and BCL-2. Defects in apoptosis can promote tumorigenesis and render malignant cells refractory to anticancer therapeutics. Activation of cell death by inhibiting antiapoptotic BCL-2 family members has emerged as an attractive strategy for cancer therapy, with the BCL-2 inhibitor venetoclax leading the way. Large-scale cancer genome analyses have revealed frequent amplification of the locus encoding antiapoptotic MCL-1 in human cancers, and functional studies have shown that MCL-1 is essential for the sustained survival and expansion of many types of tumor cells. Structural analysis and medicinal chemistry have led to the development of three distinct small-molecule inhibitors of MCL-1 that are currently undergoing clinical testing.
Highlights
Apoptosis is a genetically programmed form of cell death that removes superfluous, damaged, or dangerous cells, such as those infected with pathogens or undergoing neoplastic transformation (Green 2019, Strasser et al 2000)
Many cancers overexpress inhibitors of cell death or lack initiators of apoptosis, and these aberrations diminish the sensitivity of malignant cells to commonly used multitargeted anticancer agents, including targeted inhibitors of oncogenic kinases (Cragg et al 2009, Strasser et al 1991)
The loss of the BH3-only protein BIM or the combined loss of the apoptosis effectors BAX and BAK was shown to render cell lines derived from acute myeloid leukemia (AML), multiple myeloma, pre-B/B cell lymphoma, or certain other tumors fully resistant to the induced complete genetic deletion of Mcl-1 or treatment with MCL-1-specific BH3mimetic drugs (Caenepeel et al 2018, Glaser et al 2012, Gong et al 2016, Kotschy et al 2016)
Summary
Apoptosis is a genetically programmed form of cell death that removes superfluous, damaged, or dangerous cells, such as those infected with pathogens or undergoing neoplastic transformation (Green 2019, Strasser et al 2000). The loss of the BH3-only protein BIM or the combined loss of the apoptosis effectors BAX and BAK was shown to render cell lines derived from AML, multiple myeloma, pre-B/B cell lymphoma, or certain other tumors fully resistant to the induced complete genetic deletion of Mcl-1 or treatment with MCL-1-specific BH3mimetic drugs (Caenepeel et al 2018, Glaser et al 2012, Gong et al 2016, Kotschy et al 2016) This indicates that, at least in malignant cells, genetic loss of Mcl-1 or inhibition of MCL-1 mediated by BH3-mimetic drugs impairs survival and growth solely by unleashing apoptosis. Researchers need to understand in detail the dose-limiting toxicities of MCL-1-specific BH3-mimetic drugs and the mechanisms causing them to make progress with these drugs in the clinic
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