Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

Abstract

A hallmark of cancer is cell death evasion, underlying suboptimal responses to chemotherapy, targeted agents, and immunotherapies. The approval of the antiapoptotic BCL2 antagonist venetoclax has finally validated the potential of targeting apoptotic pathways in patients with cancer. Nevertheless, pharmacologic modulators of cell death have shown markedly varied responses in preclinical and clinical studies. Here, we review emerging concepts in the use of this class of therapies. Building on these observations, we propose that treatment-induced changes in apoptotic dependency, rather than pretreatment dependencies, will need to be recognized and targeted to realize the precise deployment of these new pharmacologic agents.

Significance: Targeting antiapoptotic family members has proven efficacious and tolerable in some cancers, but responses are infrequent, particularly for patients with solid tumors. Biomarkers to aid patient selection have been lacking. Precision functional approaches that overcome adaptive resistance to these compounds could drive durable responses to chemotherapy, targeted therapy, and immunotherapies.

Figure 1.

The BCL2 interactome. The BCL2 family of proteins is comprised of four distinct subgroups: effectors, activators, antiapoptotics, and sensitizers. Once activated, effectors BAX and BAK induce mitochondrial outer membrane permeabilization (MOMP), leading to apoptosis. In response to therapy or oncogene activation, BH3-only activators (BID, BIM, or PUMA) engage effectors, promoting cell death. Antiapoptotic proteins (BCL2, BCLXL, MCL1, BFL1/A1, and BCLW) sequester activators or effector proteins to prevent apoptosis. BH3-only sensitizers act as selective antagonists of antiapoptotic proteins. For example, BAD has high affinity for BCL2, BCLXL, and BCLW, but not for MCL1 or BFL1. In contrast, HRK selectively binds to BCLXL, and NOXA specifically binds to MCL1. When proapoptotic members outnumber antiapoptotic, the mitochondria are permeabilized by BAX/BAK releasing cytochrome c and SMAC/DIABLO to the cytosol and engaging apoptosis.

Figure 2.

Mechanisms of resistance to BH3 mimetics. For illustrative purposes, we present BCL2 as a prototypical antiapoptotic family member, BIM as a BH3-only protein, and venetoclax as the BH3 mimetic. A, The BH3 mimetic can disrupt binding of BCL2 to BIM, thereby enhancing BIM-dependent apoptosis. B, Genomic mutation that disrupts binding of the BH3 mimetic to the antiapoptotic family member. C, Microenvironmental influences such as IL10 or CD40 lead to enhanced expression of BCL2, limiting the effects of the BH3 mimetic. D, Cells adapt to conditions by upregulating alternative antiapoptotic family members, thereby reducing dependence on BCL2.

Figure 3.

Adaptive resistance to BH3 mimetics. A, In the traditional model, the dependence of each cell to each antiapoptotic BCL2 member is established, thereby predicting response to a BH3 mimetic targeting this dependency. B, However, in a heterogeneous group of cells with different BCL2 dependencies (depicted as red or green), continuous treatment with a BH3 mimetic targeting a specific dependency (with or without targeted therapy) leads to cytotoxic responses of a subset of cells. Resistant clones with a different dependency emerge in weeks to months due to impaired binding of the drug to its target. Profiling of BCL2 dependence at the time of resistance would enable rational selection of alternative therapeutic approaches. C, In an adaptive model of resistance, apoptotic BCL2 member dependence is plastic. Chemotherapy or targeted therapy induces a change in the dependency of the cell to specific BH3 mimetics within hours. Profiling of the tumor will identify the specific dependency, which can then be targeted using a specific BH3 mimetic. In this model, dependence on specific BCL2 members evolves without genomic changes. Approaches that recognize and target these rapid adaptive changes may overcome resistance. In practice, both clonal evolution and adaptive resistance contribute to resistance to BH3 mimetics, although we posit that adaptive changes are more ubiquitous.

Figure 4.

Scheme for the dynamic BH3 profiling of primary clinical samples. Tumor cells are isolated from either a solid tumor biopsy or blood. Cells are treated with an anticancer agent such as chemotherapy, targeted therapy, or a BH3 mimetic, followed by the addition of BH3 peptides. Mitochondrial depolarization (cytochrome c release) on tumor cells is analyzed by flow cytometry or microscopy. The percentage of change in priming is determined by comparing treated versus control cells, and this parameter predicts response to the agent. By using different BH3 peptides, BH3 profiling can predict response to treatment (using the BIM peptide) or changes in antiapoptotic dependencies (using specific BH3 peptides such as BAD, HRK, or NOXA/MCL1), which indicate potential combination therapies with BH3 mimetics. The overall time from biopsy to results is approximately 24 hours. Adapted from ref. and used under a CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).