What can we learn from mice lacking pro-survival BCL-2 proteins to advance BH3 mimetic drugs for cancer therapy?

Abstract

In many human cancers the control of apoptosis is dysregulated, for instance as a result of the overexpression of pro-survival BCL-2 proteins. This promotes tumorigenesis by protecting nascent neoplastic cells from stress and renders malignant cells resistant to anti-cancer agents. Therefore, several BH3 mimetic drugs targeting distinct pro-survival proteins have been developed. The BCL-2 inhibitor Venetoclax/ABT-199, has been approved for treatment of certain blood cancers and tens of thousands of patients have already been treated effectively with this drug. To advance the clinical development of MCL-1 and BCL-XL inhibitors, a more detailed understanding of their distinct and overlapping roles in the survival of malignant as well as non-transformed cells in healthy tissues is required. Here, we discuss similarities and differences in pro-survival BCL-2 protein structure, subcellular localisation and binding affinities to the pro-apoptotic BCL-2 family members. We summarise the findings from gene-targeting studies in mice to discuss the specific roles of distinct pro-survival BCL-2 family members during embryogenesis and the survival of non-transformed cells in healthy tissues in adults. Finally, we elaborate how these findings align with or differ from the observations from the clinical development and use of BH3 mimetic drugs targeting different pro-survival BCL-2 proteins.

Fig. 1. The regulation of the mitochondrial apoptotic pathway by pro-survival BCL-2 proteins.

A Schematic presentation of the structure of the different pro-survival BCL-2 proteins (not to scale). B Binding of the different pro-survival BCL-2 proteins to the different pro-apoptotic BH3-only proteins as well as the apoptosis effectors, BAX and BAK.

Fig. 2. Subcellular localisation of the pro-survival BCL-2 proteins.

Schematic presentation of the subcellular localisation of BCL-2, BCL-XL, MCL-1, A1 and BCL-W. Superscript numbers relate to the literature reference.

Fig. 3. Expression profile of pro-survival BCL-2 family members in solid tissues.

A mRNA expression of the pro-survival BCL-2 family members BCL2 (encoding BCL-2), BCL2L1 (encoding BCL-XL), MCL1 (encoding MCL-1), BCL2L2 (encoding BCL-W), BCL2A1 (encoding BFL-1) in human tissues. Data shown are from the Human Protein Atlas representing pooled Consensus Normalized eXpression (NX) levels created by combining the data from the three transcriptomics datasets (HPA, GTEx and FANTOM5) using an internal normalization pipeline [54]. B Protein expression profile of pro-survival BCL-2 family members in human tissues, quantified in a range from not detected to high expression. Data are from the Human Protein Atlas [54].

Fig. 4. mRNA expression profile of pro-survival BCL-2 family members in haematopoietic cell populations.

A Expression profile of the different pro-survival BCL-2 family members Bcl2 (encoding BCL-2), Bcl2l1 (encoding BCL-XL), Mcl1 (encoding MCL-1), Bcl2l2 (encoding BCL-W), Bcl2a1a-d (encoding A1 proteins) in different murine haematopoietic cell populations. Data are derived from the Haemopedia Mouse RNA-Seq atlas and shown in log2 transcripts per million [84]. B Expression profile of the different pro-survival BCL-2 family members BCL2 (encoding BCL-2), BCL2L1 (encoding BCL-XL), MCL1 (encoding MCL-1), BCL2L2 (encoding BCL-W), BCL2A1 (encoding BFL-1) in different human haematopoietic cell populations. Data are derived from Novershtern et al. [85] and shown as log2 normalised expression. Data for both heatmaps were sourced from www.haemosphere.org [84]. MPP – multi potential progenitor; ST-HSC - short term haematopoietic stem cell; CMP – common myeloid progenitor; GMP – granulocyte macrophage progenitor; MEP – megakaryocyte erythroid progenitor; cDC – conventional dendritic cell; pDC – plasmacytoid dendritic cell; NK cell – natural killer cell.