Finally, An Apoptosis-Targeting Therapeutic for Cancer

Abstract

Resistance to cell death represents one of the hallmarks of cancer. Various genetic and epigenetic changes in malignant cells afford cytoprotection in the face of genomic instability, oncogene activation, microenvironment stress, chemotherapy, targeted anticancer drugs, and even immunotherapy. Central among the regulators of cell life and death are Bcl-2 family proteins, with the founding member of the family (B-cell lymphoma/leukemia-2) discovered via its involvement in chromosomal translocations in lymphomas. The quest for therapeutics that target cell survival protein Bcl-2 represents a long road traveled, with many dead-ends, disappointments, and delays. Finally, a Bcl-2-targeting medicine has gained approval as a new class of anticancer agent. Cancer Res; 76(20); 5914-20. ©2016 AACR.

Figure 1. Genetic lesions accounting for dysregulation of BCL-2 gene expression in malignancies

(A):The t(14;18) and the (B) t(22;18) reciprocal chromosome translocations are depicted. The translocations juxtapose the BCL-2 gene to enhancer elements of the Ig loci causing deregulation of expression of BCL-2. (C) BCL-2 gene amplification schemes. (Top) Chromosome 18q–derived sequences are depicted with translocation to chromosome 1q32, which was further translocated to chromosomes 19 and 16. Fluorescence in situ hybridization using a chromosome 18-specific probe shows BCL-2 amplification, three labels (large arrows) in addition to normal chromosomes (small arrows). (Bottom) BCL-2 gene amplification without chromosome rearrangements (D) The 13q14 genomic region is deleted in most CLLs. The genes encoding miR-15a and miR-16-1 lie within a 30-kb deleted region between exons 2 and 5 of the DLEU2 gene. The deletion of miR-15a and miR-16-1 locus leads to Bcl-2 mRNA overexpression.

Figure 2. 3D-structure of anti-apoptotic Bcl-2 family members

The 3D-structure of the human Bcl-XL protein is depicted with an empty groove (Al; PDB accession code: 1MAZ) and in complex with the BH3 peptide from Bim (B; PDB accession code: 1PQ1). The human Bcl-2 protein is represented in complex with a modeled structure of Venetoclax based on the crystal structure of (4-(4-{[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide), a close analogue (C; PDB accession code: 4MAN). The Connolly surface of the proteins is colored by mapped atom type (carbon: white, nitrogen: blue, oxygen: red, sulfur: yellow).

Figure 3. Interactions among Bcl-2 family proteins

The categories of the Bcl-2 family are represented, including: (i) anti-apoptotic proteins, Bcl-2, Bcl-XL, Mcl-1, Bcl-W, Bfl-1, and Bcl-B (red); (ii) the multi-domain pro-apoptotic, Bax, Bak and possibly Bok (yellow), which permeabilize the outer mitochondrial membrane; (iii) BH3-only proteins that operate as both agonists of pro-apoptotic Bax/Bak and antagonists of anti-apoptotic Bcl-2 members (pink); and (iv) BH3-containing pro-apoptotic members that operate as antagonists of the anti-apoptotic proteins (orange). Tumor suppressor p53 plays important roles in responses to chemotherapy and stimulates transcription of specific pro-apoptotic members of the family (BAX, PUMA, BID, NOXA). Venetoclax is a selective antagonist of Bcl-2.