Targeting apoptotic pathways for cancer therapy
Xiaobing Tian, … , Dinara Ryspayeva, Wafik S. El-Deiry
Xiaobing Tian, … , Dinara Ryspayeva, Wafik S. El-Deiry
Published July 15, 2024
Citation Information: J Clin Invest. 2024;134(14):e179570. https://doi.org/10.1172/JCI179570.
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Review

Targeting apoptotic pathways for cancer therapy

Abstract

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.

Authors

Xiaobing Tian, Praveen R. Srinivasan, Vida Tajiknia, Ashley F. Sanchez Sevilla Uruchurtu, Attila A. Seyhan, Benedito A. Carneiro, Arielle De La Cruz, Maximilian Pinho-Schwermann, Andrew George, Shuai Zhao, Jillian Strandberg, Francesca Di Cristofano, Shengliang Zhang, Lanlan Zhou, Alexander G. Raufi, Arunasalam Navaraj, Yiqun Zhang, Nataliia Verovkina, Maryam Ghandali, Dinara Ryspayeva, Wafik S. El-Deiry

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Figure 3

Strategies targeting p53 and mutant p53.

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Strategies targeting p53 and mutant p53. (A) Reactivation of mutant p53....
(A) Reactivation of mutant p53. Direct binding of a small molecule (gray boxes) to a mutant p53 promotes and stabilizes WT p53 folding and conformation, leading to restoration of specific DNA binding and transcription of p53 target genes. This will induce tumor cell apoptosis or senescence. (B) Inhibition of MDM2. MDM2 binds to p53 directly through its N-termini and inhibits p53 function through two major mechanisms: (a) upon binding, MDM2 ubiquitinates p53, promoting proteasomal degradation of p53; (b) MDM2 promotes export of p53 out of the cell nucleus. (C) Depletion of mutant p53. Small molecules inhibit MTp53 gain-of-function and dominant-negative effects through degradation of MTp53.