Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance

Abstract

Defects in apoptosis can promote tumorigenesis and impair responses of malignant B cells to chemotherapeutics. Members of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins are key regulators of the intrinsic, mitochondrial apoptotic pathway. Overexpression of antiapoptotic BCL-2 family proteins is associated with treatment resistance and poor prognosis. Thus, inhibition of BCL-2 family proteins is a rational therapeutic option for malignancies that are dependent on antiapoptotic BCL-2 family proteins. Venetoclax (ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor that represents the first approved agent of this class and is currently widely used in the treatment of chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML). Despite impressive clinical activity, venetoclax monotherapy for a prolonged duration can lead to drug resistance or loss of dependence on the targeted protein. In this review, we provide an overview of the mechanism of action of BCL-2 inhibition and the role of this approach in the current treatment paradigm of B-cell malignancies. We summarize the drivers of de novo and acquired resistance to venetoclax that are closely associated with complex clonal shifts, interplay of expression and interactions of BCL-2 family members, transcriptional regulators, and metabolic modulators. We also examine how tumors initially resistant to venetoclax become responsive to it following prior therapies. Here, we summarize preclinical data providing a rationale for efficacious combination strategies of venetoclax to overcome therapeutic resistance by a targeted approach directed against alternative antiapoptotic BCL-2 family proteins (MCL-1, BCL-xL), compensatory prosurvival pathways, epigenetic modifiers, and dysregulated cellular metabolism/energetics for durable clinical remissions.

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies

“…B-cell lymphoma-2 (BCL-2) proteins regulate the intrinsic mitochondrial apoptotic pathway and represent another therapeutic target in B-cell malignancies (66). Venetoclax is an approved, highly selective BCL-2 inhibitor used in treatment of patients with CLL.…”

Novel Agents in Chronic Lymphocytic Leukemia: New Combination Therapies and Strategies to Overcome Resistance

“…Under the influence of BTK inhibition by targeted drugs, CLL cells and malignant B-cells in other lymphoid neoplasms may adapt and compensate for the blocked BTK axis by activating the PI3K/Akt/Erk pathway [ 21 , 22 , 41 ]. Functional analyses by Spina et al in cells from ibrutinib-treated patients revealed that the BCR pathway through Akt and Erk was still inducible upon stimulation of the B-cell receptor in spite of effective inhibition of the BTK/PLCy2 pathway [ 22 ].…”

The p62/Keap1/Nrf2 axis in the control of C-2 induced human gastric cancer cell death switching between autophagy and apoptosis

“…Two key members of MAPK family, JNK (c-Jun N-terminal kinase) and ERK (extracellular signal-regulated kinase), can dissociate Bcl-2/Beclin-1 or Bcl-xL/Beclin-1 complexes to release Beclin-1, resulting in autophagy. Bcl-2 and Bcl-xL belong to anti-apoptotic Bcl-2 protein family, levels of which will be decreased during apoptosis [14].…”