What can we learn from mice lacking pro-survival BCL-2 proteins to advance BH3 mimetic drugs for cancer therapy?
- Author(s)
- Brinkmann, K; Ng, AP; de Graaf, CA; Strasser, A;
- Details
- Publication Year 2022-04-06,Volume 29,Issue #6,Page 1079-1093
- Journal Title
- Cell Death and Differentiation
- 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.
- Publisher
- NPG
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 35388168
- Publisher's Version
- https://doi.org/10.1038/s41418-022-00987-0
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-04-11 11:15:09
Last Modified: 2022-06-16 11:01:53