Principles for understanding mechanisms of cell death and their role in cancer biology in Precision Cancer Therapies, Volume 1 Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies
- Author(s)
- Diepstraten, ST; Marca, JEL; Huang, DCS; Kelly, GL;
- Journal Title
- Precision Cancer Therapies
- Publication Type
- Book Chapter
- Abstract
- Cell death is a critical physiological process needed to remove damaged, infected, or superfluous cells. It is estimated that in an average human up to 330 billion cells die and are replaced with new cells each day (Sender and Milo 2021). This, alongside other tumor suppressive processes, ensures that unwanted or damaged cells that could form tumors are safely and efficiently destroyed. As such, evasion from cell death is a key hallmark of malignant diseases (Hanahan and Weinberg 2011) and can arise through many different mechanisms (Kelly and Strasser 2011), resulting in reduced sensitivity to developmental cues and permitting the expansion of cancerous cells. Understanding the pathways to cell death and the different ways cancer cells can disable the cell death machinery can inform the most effective ways to treat a particular cancer. Many anti-cancer therapies act to induce cell death preferentially in cancer cells, often through induction of DNA damage which activates the critical tumor suppressor protein, TP53. Activated TP53 then serves to block tumor growth by upregulation of hundreds of target genes involved in diverse cellular pathways, including DNA repair, cell cycle arrest, cellular senescence, and a form of programmed cell death termed apoptosis (Aubrey et al. 2018; Lieschke et al. 2018; Yonish-Rouach et al. 1991). In recent years, anti-cancer therapeutics that aims to induce cell death through direct manipulation of key components of the apoptosis pathway downstream of TP53 has been developed. These drugs are termed BH3-mimetics, because they mimic the function of the natural pro-apoptotic BH3-only proteins (e.g. BIM and PUMA) that are critical for the induction of apoptosis signaling. BH3 mimetic drugs work by directly inhibiting key apoptosis inhibitory proteins (called pro-survival B-cell lymphoma 2 [BCL2] proteins), such as BCL2 or mantle cell lymphoma 1 (MCL-1), to trigger cancerous cells to undergo apoptosis (Diepstraten et al. 2022; Merino et al. 2018). Knowledge about which pro-survival BCL2 protein is essential for the growth of a particular cancer is therefore critical for the application of BH3-mimetic drugs in cancer patients. Subsequent chapter will focus on the pre-clinical and clinical application of BH3 mimetic drugs for cancer therapy. Here, we endeavor to provide a basic explanation of the cellular apoptotic cell death pathway that these drugs target and provide a historical perspective of where the field started, the critical discoveries that led to the expansion of this field of research, and ultimately led to these new anti-cancer drugs for patients. © 2023 John Wiley & Sons, Inc. All rights reserved.
- Publisher
- Wiley
- Keywords
- Apoptosis; BCL2; BH3-proteins; Cell survival
- Research Division(s)
- Blood Cells And Blood Cancer
- Publisher's Version
- https://doi.org/10.1002/9781119819950.ch10
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-06-30 02:15:59
Last Modified: 2023-06-30 02:30:26