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

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Kerstin Brinkmann1,2, Ashley P Ng3,4, Carolyn A de Graaf3,4

  • 1The Walter and Eliza Hall Institute of Medical Research, Melbourne, Vic, Australia. brinkmann.k@wehi.edu.au.

Cell Death and Differentiation
|April 7, 2022
PubMed

Insights

Dysregulated apoptosis, driven by pro-survival BCL-2 proteins, fuels cancer. Understanding these proteins

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Dysregulation of apoptosis, often due to overexpression of pro-survival BCL-2 proteins, is a hallmark of many human cancers.
  • This overexpression promotes tumorigenesis by protecting cancer cells from stress and conferring resistance to anti-cancer therapies.
  • BH3 mimetic drugs targeting pro-survival proteins offer a therapeutic strategy, with Venetoclax (a BCL-2 inhibitor) already approved for certain blood cancers.

Purpose of the Study:

  • To advance the clinical development of MCL-1 and BCL-XL inhibitors.
  • To gain a detailed understanding of the distinct and overlapping roles of MCL-1 and BCL-XL in malignant cells and non-transformed cells in healthy tissues.
  • To compare the structure, subcellular localization, and binding affinities of pro-survival BCL-2 proteins with pro-apoptotic family members.

Main Methods:

  • Review of structural and functional similarities/differences among pro-survival BCL-2 proteins.
  • Summarization of findings from gene-targeting studies in mice.
  • Analysis of clinical data from BH3 mimetic drug development and use.

Main Results:

  • Pro-survival BCL-2 proteins share structural similarities but exhibit distinct roles in embryogenesis and adult tissue homeostasis.
  • Gene-targeting studies in mice reveal specific functions of MCL-1 and BCL-XL in normal cell survival.
  • Clinical data highlight varying efficacy and toxicity profiles of BH3 mimetics targeting different pro-survival proteins.

Conclusions:

  • A comprehensive understanding of pro-survival BCL-2 protein biology is crucial for optimizing BH3 mimetic cancer therapy.
  • Distinct roles of MCL-1 and BCL-XL in normal tissues necessitate careful consideration for targeted drug development.
  • Aligning preclinical findings with clinical observations will guide the rational design and application of novel BH3 mimetics.

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