Review Open Access | 10.1172/JCI179570

Xiaobing Tian,1,2,3,4 Praveen R. Srinivasan,1,2,3,4 Vida Tajiknia,1,2,3,4 Ashley F. Sanchez Sevilla Uruchurtu,1,2,3,4,5 Attila A. Seyhan,1,2,3,4 Benedito A. Carneiro,1,3,4,6 Arielle De La Cruz,1,2,3,4 Maximilian Pinho-Schwermann,1,3,4,6 Andrew George,1,2,3,4 Shuai Zhao,1,2,3,4 Jillian Strandberg,1,2,3,4 Francesca Di Cristofano,1,2,3,4 Shengliang Zhang,1,2,3,4 Lanlan Zhou,1,2,3,4 Alexander G. Raufi,1,3,4,6 Arunasalam Navaraj,1,2,3,4 Yiqun Zhang,1,2,3,4 Nataliia Verovkina,1,2,3,4 Maryam Ghandali,1,2,3,4 Dinara Ryspayeva,1,2,3,4 and Wafik S. El-Deiry1,2,3,4,5,6

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

Find articles by Tian, X. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

Find articles by Zhang, S. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

Find articles by Navaraj, A. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

Find articles by Zhang, Y. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

Find articles by Verovkina, N. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

Find articles by Ghandali, M. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

Find articles by Ryspayeva, D. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Experimental Cancer Therapeutics and

2Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

3Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

4Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.

5Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.

6Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, Rhode Island, USA.

Address correspondence to: Wafik S. El-Deiry, Warren Alpert Medical School, Brown University, Department of Pathology and Laboratory Medicine, Campus Box G-E5, 70 Ship Street, Room 537, Providence, Rhode Island 02903, USA. Email: wafik@brown.edu. Or to: Xiaobing Tian, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University

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Published July 15, 2024 - More info

Published in Volume 134, Issue 14 on July 15, 2024
J Clin Invest. 2024;134(14):e179570. https://doi.org/10.1172/JCI179570.
© 2024 Tian et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. View PDF 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.

Introduction

Apoptosis is a form of regulated cell death with a critical role in development and homeostasis (1). Activation of apoptotic pathways results in destruction of target cells with minimal inflammatory response and disruption to surrounding tissue. Preventing cancer is an important function of apoptosis (2), and dysregulation and evasion of apoptosis are hallmarks of cancer. Tumor cells employ multiple mechanisms to evade apoptosis, including expression of apoptosis inhibitors as a means of acquiring resistance to cancer therapies. Much effort has gone into developing drugs to reinstate or promote apoptosis in cancer cells. Below, we will briefly describe the major apoptotic pathways, then highlight major advancements toward targeting these pathways and other regulators of apoptosis in cancer cells.

Intrinsic and extrinsic apoptotic pathways

Two pathways are considered the major drivers of apoptosis in all cells: the intrinsic pathway, initiated by the formation of Bax and Bak pores on the mitochondrial outer membrane (MOM), and the extrinsic pathway, triggered by death receptors (DRs) on the plasma membrane (Figure 1).

Figure 1

Intrinsic and extrinsic apoptosis pathways. (A) Intrinsic apoptosis pathways. Upon activation, BAK and BAX undergo conformational changes and oligomerization, forming pores in the MOM and causing irreversible MOM permeabilization (MOMP), the critical step for intrinsic apoptosis (3), allowing release of cytochrome c and SMAC. Cytochrome c and dATP join APAF-1 and the initiator protein procaspase-9 to form the apoptosome, while SMAC interacts with IAPs (see below). Within the apoptosome, procaspase-9 is cleaved into active caspase-9, which cleaves and activates the apoptosis effector proteins caspase-3, -6, and -7 (3). (B) Extrinsic apoptosis pathway. Upon ligand binding, DR4 and DR5 trimerize and aggregate within the cell membrane, a process known as capping. This is followed by recruitment of the adaptor protein FADD, which has a death effector domain (DED). Initiator procaspase-8 and -10 also have DEDs that bind to FADD at its DED, forming the DISC. Procaspase-8 and -10 are activated within the DISC and in turn cleave and activate executioner caspase-3, -6, and -7. Activation of procaspase-8/10 is negatively regulated by c-FLIP. c-FLIP competes directly with procaspase-8 for binding to FADD through homotypic DED interactions, thus inhibiting procaspase-8 recruitment and activation at the DISC (9-12). Activated caspase-8 also cleaves the BH3 subfamily member BID to active form truncated-BID (tBID). tBID translocates to the MOM and initiates apoptosis through its interactions with proapoptotic effector proteins BAK and BAX. BID cleavage and translocation to the mitochondria link the extrinsic cell death pathway to the intrinsic apoptotic pathway and amplify the apoptotic response. This amplification mechanism is required for effective apoptosis in certain cells, denoted as type II cells for their mechanism of apoptosis, in contrast with type I cells, which undergo extrinsic apoptosis independently of intrinsic apoptosis pathway induction (13, 14).

Intrinsic apoptosis

In most mammalian cells, the B cell lymphoma 2 (BCL-2) protein family regulates the intrinsic pathway (Figure 1A) (3). BCL-2 family members are characterized by the presence of up to four distinct segments of amino acid homology, termed BCL-2 homology (BH) domains. The interactions of the BCL-2 protein family are depicted in detail in Figure 2A (3–8).

Figure 2

Targets in the intrinsic and extrinsic apoptosis pathways. (A) Interactions of the BCL-2 protein family. The multi-BH domain family members either suppress apoptosis (e.g., BCL-2, BCL-XL, and MCL-1) or promote apoptosis (e.g., BAX, BAK), whereas the BH3-only subfamily members identified to date (e.g., BAD, BID, PUMA, NOXA, and BIM) function exclusively to promote cell death (3, 4) BH3-only proteins can be divided into activators or sensitizers. The activators PUMA, tBID, and BIM directly activate BAK and BAX and interact with antiapoptotic proteins to promote MOMP (5, 6). In contrast, the sensitizers BAD and NOXA only interact with the antiapoptotic proteins and do not activate BAK and BAX (7, 8). Interactions with antiapoptotic BCL-2 proteins and activator BH3-only proteins regulate BAK and BAX activity. (B) High-potency TRAIL receptor agonists. ABBV-621 is a hexavalent TRAIL fusion protein with Fc-FcγR interactions disabled by IgG Fc D297S mutation. INBRX-109 is a tetravalent DR5 agonistic antibody with Fc effector function disabled by forming a cycle.

Extrinsic apoptosis

Perturbations of the extracellular microenvironment that trigger release of Fas-L, TNF, and TRAIL activate the extrinsic apoptotic pathway when these extracellular ligands bind to Fas, TNF receptors, and DR4/5, respectively. As ongoing efforts in anticancer drug discovery and development continue to focus on targeting DR4/5, we will focus on their role in apoptosis here. The mechanism of DR4/5 activation is summarized in Figure 1B (9–14).

IAPs and execution of apoptosis

Inhibitors of apoptosis (IAPs) constitute a highly conserved family of proteins defined by the presence of 1–3 protein motifs called baculovirus IAP repeats (BIRs). Most BIRs form a surface hydrophobic groove that specifically binds a conserved tetrapeptide motif, called IAP-binding motif (IBM), found in the active subunits of caspase-3, -7, and -9 (15). Second mitochondrial activator of caspase (SMAC) released by MOM permeabilization blocks IAPs (including XIAP) to promote cell death (16) (Figure 1A). Caspases-3, -6, and -7 execute apoptosis via the proteolysis of thousands of cellular proteins. The main features of cells undergoing apoptosis include chromatin condensation, DNA fragmentation, membrane blebbing, and cytoskeletal rearrangement (4).

Targeting intrinsic apoptosis in cancer therapy

Cancer cells resist apoptosis using a variety of mechanisms. Defects in intrinsic pathways include the following: (a) acquiring of caspase gene mutations that inhibit caspase function (2); (b) overexpression of antiapoptotic BCL-2 family proteins (2, 15); (c) overexpression of IAPs (17); (d) loss and inactivation of apoptotic effectors BAX and BAK (2, 18); (e) insufficient release of cytochrome c and mutation of lysine residues (especially K72) of cytochrome c that abrogate the apoptosome formation, causing inhibition of caspase activation (19, 20); and (f) defects in extrinsic pathway signaling. These defects include (a) overexpression of apoptosis-inhibiting decoy receptors (e.g., DcR1/2), which compete with DR4/5 for TRAIL binding (21); (b) decreased DR4/5 activity; and (c) death-inducing signaling complex (DISC) inhibition by FLICE-like inhibitory protein (c-FLIP) (22). For instance, colorectal cancer (CRC) cells have decreased activity of DR4/5 that contributes to their resistance to apoptosis (21, 23). Decreased expression of DR4/5 seems to result from defective p53, impaired transport from ribosomes, defective redistribution of DR4/5 in lipid rafts and mutations, epigenetic changes (23, 24, or overexpression of DcR3.

Tumor cells can overexpress multiple inhibitors of both apoptotic pathways, including in the process of acquiring resistance to cancer therapy. Upregulation of the antiapoptotic BCL-2 family proteins and decreased expression of proapoptotic proteins are responsible for cancer cell resistance to chemotherapy and radiation. For example, BCL-2 gene expression is elevated in over half of all cancers and XIAP is overexpressed in many tumors (2, 4, 17).

Recent development of apoptosis-targeted drugs has focused on the intrinsic pathway, including BCL-2, MCl-1, and IAP inhibitors (25). In this Review, we focus our discussion on BCL-2–specific inhibitors due to the relatively recent approval of the BCL-2 inhibitor venetoclax by the US FDA.

Venetoclax

BCL-2 inhibitors, also known as BH3 mimetics, are among the frontrunners of agents that were developed as a targeted approach to directly alter the intrinsic apoptosis pathway. BH3 mimetics are small molecules that mimic the binding of BH3-only proteins to the hydrophobic pockets within antiapoptotic BCL-2 proteins. In 2016, venetoclax (ABT-199) was the first agent targeting BCL-2 to be approved by the US FDA for the treatment of patients with chronic lymphocytic leukemia (CLL) harboring 17p deletion. Venetoclax binds to BCL-2, leading to the release of BIM, which in turn directly activates BAX and BAK (26–28) (Table 1 and Figure 2A). In May 2019, venetoclax was approved by the FDA for the frontline treatment of patients with CLL owing to the superior efficacy of venetoclax plus the anti-CD20 antibody obinutuzumab over chlorambucil plus obinutuzumab, thus providing a chemotherapy-free option for CLL patients (29). Venetoclax was also approved by the FDA in 2020 for the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for standard induction chemotherapy (i.e., >75 years old) (30, 31).

Table 1

Targeting intrinsic and extrinsic apoptosis

Targeting extrinsic apoptosis in cancer therapy

TRAIL analogs

TRAIL is a transmembrane trimeric glycoprotein that can be cleaved by metalloproteinases and released as a soluble factor (32, 33). Both soluble and membrane-bound forms of TRAIL can bind to DR4/5, triggering the extrinsic apoptosis pathway (Figure 1A). TRAIL signaling selectively induces cancer cell apoptosis without causing toxicity to normal cells. Based on this unique activity profile, many agents targeting this pathway, including recombinant human TRAIL (rhTRAIL, or dulanermin) and DR4/5 agonist antibodies (lexatumumab and conatumumab for DR5, mapatumumab for DR4), have been developed and evaluated in vitro and in vivo (34–37). Preclinical data indicated that both classes of molecules are generally well tolerated, but ultimately, they showed limited anticancer activity in patients. One factor contributing to limited anticancer activity is rhTRAIL’s very short half-life in blood, from 0.56 to 1.02 hours (38, 39). Although rhTRAIL induces trimerization (also known as lower-order trimerization) of DR4/5, its soluble form of TRAIL has limited capacity to induce high-order clustering of the DR trimers, resulting in a weak apoptotic signal (40). For DR4/5 agonist antibodies, lower-order receptor trimerization is a major limitation due to the bivalent structure of the antibodies (40,