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Targeting IAP proteins for therapeutic intervention in cancer

A Corrigendum to this article was published on 30 March 2012

This article has been updated

Key Points

  • Inhibitor of apoptosis (IAP) proteins are a family of anti-apoptotic proteins that promote cancer cell survival and inhibit cell death.

  • IAP proteins represent promising targets for therapeutic intervention in human cancers, as they are expressed at high levels in various malignancies and have been linked to tumour progression, treatment failure and poor prognosis.

  • Several therapeutic strategies have been designed in recent years to target IAP proteins, including second mitochondria-derived activator of caspase (SMAC)-mimicking IAP antagonists.

  • Preclinical studies indicate that the therapeutic potential of IAP antagonists might best be exploited in combination protocols, including conventional chemotherapeutics, death receptor agonists, signal transduction modulators or radiation therapy.

  • IAP antagonists have already entered the clinical stage and are currently being evaluated in early-stage clinical trials.

Abstract

Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases — pro-apoptotic executioner proteases — whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.

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Figure 1: Cell death pathways.
Figure 2: Canonical and non-canonical NF-κB signalling pathways.
Figure 3: Structure and development status of selected IAP antagonists.
Figure 4: Model for the induction of c-IAP protein ubiquitin ligase activity by IAP antagonists.

Change history

  • 30 March 2012

    The chemical structure of the clinical candidate TL32711 in Figure 3 was incorrectly represented. The authors apologize for this unintended error.

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Acknowledgements

We thank W. Fairbrother, K. Deshayes, E. Dueber and other researchers at Genentech who provided help with comments, figures and suggestions; we also thank C. Hugenberg for expert secretarial assistance. This work has been partially supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft), the Federal Ministry of Education and Research (BMBF), the José Carreras Foundation, the European Commission and IAP6/18 (to S.F.).

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Correspondence to Simone Fulda or Domagoj Vucic.

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Domagoj Vucic is an employee of Genentech.

Supplementary information

Supplementary information S1 (table)

Role of IAP proteins in cancer (PDF 211 kb)

Supplementary information S2 (table)

Combination treatments with IAP antagonists (PDF 221 kb)

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FURTHER INFORMATION

Simone Fulda's homepage

Domagoj Vucic's homepage

ClinicalTrials.gov website (A Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC-0917 Administered to Patients With Refractory Solid Tumors or Lymphoma)

Glossary

Inhibitor of apoptosis

(IAP). An anti-apoptotic protein family that encompasses the caspase inhibitor X chromosome-linked IAP and the regulators of nuclear factor-κB signalling — the cellular IAPs.

Baculoviral IAP repeat

(BIR). A signature zinc ion-coordinating domain that is crucial for caspase inhibition and many protein–protein interactions.

RING domain

A ubiquitin ligase domain defined by a catalytic zinc finger-like module that coordinates two zinc ions.

IAP antagonists

Molecules that bind to inhibitor of apoptosis (IAP) proteins and block IAP-mediated inhibition of cell death.

Extrinsic (death receptor) pathway of apoptosis

An apoptotic pathway initiated at the plasma membrane by specific transmembrane receptors of the tumour necrosis factor receptor superfamily. Ligation of these receptors results in the formation of a death-inducing signalling complex that drives caspase 8 activation.

Intrinsic (mitochondrial) pathway of apoptosis

An apoptotic pathway that is triggered by cellular stresses (such as DNA damage) or intracellular stimuli (such as the production of reactive oxygen species or calcium overload).

Tumour necrosis factor

(TNF). A cytokine that is involved in systemic inflammation and is necessary for the single-agent pro-apoptotic activity of inhibitor of apoptosis protein antagonists.

Second mitochondria-derived activator of caspase

(SMAC). A pro-apoptotic protein that leaves mitochondria and enters the cytoplasm following apoptotic insult; in the cytoplasm, it binds to and neutralizes inhibitor of apoptosis proteins.

Nuclear factor-κB

(NF-κB). A protein complex that regulates the expression of several cytokines and anti-apoptotic proteins. NF-κB signalling proceeds via the canonical or non-canonical pathways.

Canonical NF-κB pathway

A signalling pathway mediated by nuclear factor-κB (NF-κB) that predominantly results in the activation of transcription factor RELA (also known as p65)–p50 heterodimers.

Non-canonical NF-κB pathway

A signalling pathway mediated by nuclear factor-κB (NF-κB) that predominantly results in the activation of transcription factor RELB–p52 heterodimers.

Duke's staging

Classification system for colorectal cancer based on pathology.

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Fulda, S., Vucic, D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11, 109–124 (2012). https://doi.org/10.1038/nrd3627

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