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Review
. 2018 Oct 22:8:458.
doi: 10.3389/fonc.2018.00458. eCollection 2018.

Hematologic Tumor Cell Resistance to the BCL-2 Inhibitor Venetoclax: A Product of Its Microenvironment?

Joel D Leverson  1 , Dan Cojocari  2
Affiliations
Review

Hematologic Tumor Cell Resistance to the BCL-2 Inhibitor Venetoclax: A Product of Its Microenvironment?

Joel D Leverson et al. Front Oncol. .

Abstract

BCL-2 family proteins regulate the intrinsic pathway of programmed cell death (apoptosis) and play a key role in the development and health of multicellular organisms. The dynamics of these proteins' expression and interactions determine the survival of all cells in an organism, whether the healthy cells of a fully competent immune system or the diseased cells of an individual with cancer. Anti-apoptotic proteins like BCL-2, BCL-XL, and MCL-1 are well-known for maintaining tumor cell survival and are therefore attractive drug targets. The BCL-2-selective inhibitor venetoclax has been approved for use in chronic lymphocytic leukemia and is now being studied in a number of other hematologic malignancies. As clinical data mature, hypotheses have begun to emerge regarding potential mechanisms of venetoclax resistance. Here, we review accumulating evidence that lymphoid microenvironments play a key role in determining hematologic tumor cell sensitivity to venetoclax.

Keywords: BCL-2; microenvironment; resistance; tumor; venetoclax.

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Figures

Figure 1
Figure 1
(A) The intrinsic (mitochondrial) pathway of apoptosis is regulated by structurally related proteins in the BCL-2 family, which share from one to four BCL-2 homology (BH1-BH4) motifs. These proteins can be sub-classified as anti-apoptotic (pro-survival) or pro-apoptotic (pro-death). Pro-apoptotic proteins can be further sub-divided into multi-BH effector proteins (BAX, BAK, BOK) and so-called BH3-only proteins. Certain BH3-only proteins like BIM can bind and allosterically activate effector proteins, promoting their insertion into mitochondrial membranes and subsequent oligomerization. Other BH3-only proteins, such as NOXA, can act as sensitizers of apoptosis by binding to anti-apoptotic proteins and precluding their sequestration of pro-apoptotic effectors and activators. (B) Anti-apoptotic proteins bind the BH3 motifs (depicted as small, green rectangles) of specific pro-apoptotic proteins, thereby sequestering them and preventing the initiation of apoptosis. Each pro-apoptotic protein demonstrates its own selectivity profile regarding which anti-apoptotic protein(s) it tends to associate with. (C) Synthetic small-molecule “BH3 mimetics” (depicted as small, yellow rectangles) like venetoclax are designed to bind certain anti-apoptotic proteins and compete for binding with pro-apoptotic proteins. Pro-apoptotic proteins liberated by BH3 mimetics are free to initiate the key molecular events of programmed cell death, including effector activation, mitochondrial outer membrane permeabilization (MOMP), the release of apoptogenic factors like cytochrome c (depicted as small red circles) into the cytosol, the proteolytic activation of caspases and the dismantling of the cell.
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