Key Points
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The development of kinase inhibitors — which predominantly target kinases that are dysregulated in various cancers — is a rapidly growing area of drug discovery.
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The vast majority of approved kinase inhibitors and drugs in development target the ATP binding pocket. However, the conservation of the ATP binding pocket among kinases can mean that inhibitors can also inhibit unintended kinases, and if any of these kinases serve important functions in the heart, off-target cardiotoxicity can result.
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Many of the pathways that regulate cancer cell survival also regulate essential processes in cardiomyocytes, including survival. So, although inhibiting those kinases in the cancer is beneficial, inhibiting them in the cardiomyocyte may not be.
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Although clinically important cardiotoxicity appears to be limited to only a few currently marketed agents, a big concern is the large number of drugs in development, many of which are multi-targeted and either intentionally or unintentionally inhibit pathways that maintain cardiomyocyte homeostasis. Thus, it is imperative to develop strategies that accurately identify problematic agents early in the drug development process.
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In this Review we discuss the growing connection between preclinical models of kinase inhibitor-induced cardiotoxicity and clinical safety. We discuss the challenges of making safe and selective inhibitors of a kinase by examining the cardiac effects of sunitinib. We also explore the field of genetically modified mouse models and discuss their merits in predicting more effectively which kinase inhibitors may have the potential to cause cardiotoxicity. Additionally in vitro models used to predict cardiotoxicity are reviewed, with emphasis on human stem cell-derived cardiomyocytes. Lastly, we conclude with future perspectives on clinical studies, including biomarkers and imaging.
Abstract
Targeted therapeutics, particularly those that inhibit the activity of protein kinases that are mutated and/or overexpressed in cancer, have revolutionized the treatment of some cancers and improved survival rates in many others. Although these agents dominate drug development in cancer, significant toxicities, including cardiotoxicity, have emerged. In this Review, we examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of small molecule kinase inhibitors. We also discuss how well the various preclinical safety models and strategies might predict clinical cardiotoxicity. It is hoped that a thorough understanding of the mechanisms underlying cardiotoxicity will lead to the development of safe, effective drugs and consequently, fewer costly surprises as agents progress through clinical trials.
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Thomas Force is a consultant to GlaxoSmithKline, for issues surrounding cardiotoxicity of kinase inhibitors.
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Glossary
- Regular type radionuclide ventriculography
-
The use of radionuclides to study left ventricular function.
- Multi-targeted
-
Intentionally designed kinase inhibitor of more than one kinase.
- Cardiac stress
-
Either increased demand (for example, hypertension) or reduced supply (for example, ischaemia) of oxygen to the heart.
- Class effect
-
A toxicity or pharmacological outcome that occurs with all molecules that inhibit a particular target (for example, all β-adrenergic receptor antagonists lead to heart rate slowing).
- Side population
-
A form of stem cell that is characterized by a specific pattern using fluorescent activated sorting.
- Hoechst dye
-
A family of fluorescent stains used for labelling DNA and detecting and/or separating cell populations of interest.
- Pressure load
-
A pressure load on the heart can be induced by anything that raises blood pressure. Experimentally, this typically means constricting the transverse aorta or infusing a drug (for example, angiotensin II).
- Mitochondrial permeability transition pore
-
A regulatory opening within the mitochondria induced by certain types of cellular stress (for example, oxidant stress or ischemia). This results in loss of mitochondrial membrane integrity and swelling, ultimately inducing cell death.
- Stem/progenitor cell compartment
-
The small population of undifferentiated cells within a tissue that has the potential to regenerate and replenish the dying cells of an organ.
- Anthracycline
-
A class of drugs (of which doxorubicin is a member) used extensively in treatment of various cancers.
- Pressure overload
-
A consequence of thoracic aortic constriction, resulting in increased blood pressure and subsequent cardiac hypertrophy and LV dysfunction.
- Thoracic aortic constriction
-
A surgical procedure in which the aorta is banded, creating an acute and usually severe increase in blood pressure.
- HERG
-
The human ether-a-go-go gene HERG (also known as KCNH2) codes for a specific potassium ion channel. Mutations in the gene cause one form of hereditary long QT syndrome.
- Phenocopies
-
A phenotype or trait that is similar among different individuals.
- Noonan, Costello and Cranio-facio-cutaneous syndromes
-
A group of syndromes that affect a number of organ systems and cause severe cardiac hypertrophy.
- Ischaemia–reperfusion injury
-
A complex phenomenon that occurs when the blood supply from an organ is restored after a period of ischaemia.
- Endoplasmic reticulum stress
-
A conserved response to excessive misfolded proteins resulting in an effort to repair and correct the situation; failing to do so leads to programmed cell death.
- ABL
-
An oncogene associated with chronic myelogenous leukaemia.
- Embyroid bodies
-
Aggregates of differentiating and undifferentiated cells formed from embryonic stem cells.
- IKr
-
The inward delayed rectifier potassium current that is regulated in humans by HERG and is responsible for repolarization of cardiac action potential.
- Tissue Doppler imaging/strain rate
-
A form of cardiac ultrasound used to assess functional parameters of the direction and speed of blood flow.
- Hazard ratio
-
An explanatory factor used to assess the risk of a given event or disease.
- B-type natriuretic peptide
-
A protein secreted from the heart in response to stress, including stretch.
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Force, T., Kolaja, K. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov 10, 111–126 (2011). https://doi.org/10.1038/nrd3252
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DOI: https://doi.org/10.1038/nrd3252
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