BH3 Mimetics in Hematologic Malignancies

Abstract

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action-direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.

Keywords: BH3 mimetics; apoptosis; biomarkers; hematologic malignancies; resistance; targeted therapy; venetoclax.

Figure 1

Overview of mammalian proteins of the BCL2 family. Multidomain anti-apoptotic and pro-apoptotic BCL2-homology (BH) BH1-BH4 domains, and transmembrane (TM) domains are shown as opaque; presumed BH and TM domains are shown as transparent. PEST—signal peptide for protein degradation.

Figure 2

Selected BH3 mimetics targeting the anti-apoptotic BCL2 family proteins. (A) Molecular formulas of representative BH3 mimetics binding to/blocking BCL2/BCL-XL (navitoclax), BCL2 (venetoclax), MCL1 (S63845), or BCL-XL (A1155463); (B) Graphical representation of navitoclax and its binding to the hydrophobic groove of BCL2 protein (P2, P4—navitoclax-binding BCL2 hydrophobic pockets). Reproduced from [65] with permission from Springer Nature publishing house.

Figure 3

Mechanisms of venetoclax-triggered apoptosis in cells primed for death. (A) Cells primed for death: anti-apoptotic BCL2 proteins (BCL2, BCL-XL, MCL1) are fully occupied by pro-apoptotic BH3-only proteins (BIM, BAD, NOXA); (B) Venetoclax causes displacement of BIM from BCL2 with subsequent assembly of BAX/BAK1 multiprotein complex, mitochondrial outer membrane permeabilization and release of cytochrome c and activation of apoptosis.

Figure 4

Mechanisms of resistance to venetoclax. (A) Mutation of BCL2 prevents binding of venetoclax to BCL2; (B) Adaptive overexpression of BCL-XL and/or MCL1 leads to sequestration of BIM released from BCL2; (C) Loss of NOXA or BIM attenuates the potential of venetoclax to trigger apoptosis; (D) BAX mutations prevent activation of mitochondrial apoptosis; (E) TP53 aberrations block mitochondrial apoptosis and facilitate selection of venetoclax resistance clones; (F) Other mechanisms include multiple genetic, epigenetic, and metabolic changes, the role of which in mediating venetoclax resistance are only partially understood.

Figure 5

Mechanisms of anti-leukemic synergy between venetoclax and hypomethylating agents. (A) HMA-induced expression of pro-apoptotic genes PMAIP1 (coding for NOXA, yellow) and PUMA (green); (B) HMA-induced downregulation of anti-apoptotic MCL1 protein; (C) Venetoclax-induced suppression of oxidative phosphorylation (Ox/Phos); (D) Venetoclax-mediated increase in production of reactive oxygen species (ROS); (E) Venetoclax-induced alteration of mitochondrial structure; (F) Venetoclax-mediated increase in expression of CD25 and NKG2D on T cells [107,111,112,113].