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Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Key Points

  • Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several malignancies, converting lethal diseases into manageable, if not curable, chronic diseases. This makes it essential to limit toxicities of these agents.

  • The goal of tumour-cell killing by TKIs must be balanced against cardiotoxicity, because in some instances tumour cell death and preservation of cardiomyocyte health may be mutually exclusive.

  • Cardiomyocytes are contractile and have an extremely high demand for ATP. As a result, they might be particularly susceptible to agents that perturb mitochondrial function, either as a primary or secondary effect. Therefore, alterations in mitochondrial function could have a role in the cardiotoxicities of some currently approved agents.

  • Very few clinical trials have examined cardiotoxicities of TKIs in a prospective fashion with predefined cardiac endpoints, including left ventricular function. Therefore, there is a wide gap in our knowledge regarding the types of, and risk of, cardiotoxicity for most of these agents.

  • Some current kinase targets in cancer are not expressed in cardiomyocytes and therefore have little or no direct role in cardiomyocyte survival. However, the current generation of TKIs is inherently non-selective, and the purposeful design of multi-targeted TKIs might allow a single agent to be more effective, and to be used in more types of cancer, but with this comes an increased risk of cardiotoxicity. In some cases this will probably be due to inhibition of 'bystander' targets that are not essential for the killing of tumour cells but that are involved in cardiomyocyte survival.

  • Identification of the kinase that, when inhibited, is responsible for cardiotoxicity of an agent is important for future drug design, which should avoid these kinases where possible. Thus, greater selectivity of individual agents may require the use of more agents to treat a particular cancer, but cardiotoxicity as an 'off-target' effect should be minimized.

Abstract

Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of 'targeted therapies', particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.

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Figure 1: ERBB2 signalling and inhibition in breast cancer and cardiomyocytes.
Figure 2: ABL signalling and inhibition in chronic myeloid leukaemia cells and cardiomyocytes.
Figure 3: Potential role of off-target effects in mediating cardiotoxicity of multi-targeted tyrosine kinase inhibithors.
Figure 4: Putative signalling pathways of sorafenib cardiotoxicity.

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Acknowledgements

We thank R. Kerkela, K. Woulfe, M.-H. Chen and M. Rupnick for their contributions to this work. The work was supported by grants from the National Heart Lung and Blood Institute (to T.F.) and a SCOR (Specialized Centers of Research) grant from the Leukemia and Lymphoma Society (to R.A.V.). We want to point out that the highlighted references focus predominantly on mechanisms of cardiotoxicity and, therefore, there are many papers describing major advances in oncology that are not highlighted.

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Correspondence to Thomas Force.

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Thomas Force is a consultant for Novartis Pharmaceuticals, Inc. and he is on the Speakers' Bureau for Merck & Co. Inc.

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FURTHER INFORMATION

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Glossary

Cardiomyocytes

The contractile cells of the heart that generate force. These cells are terminally differentiated and so cardiomyocytes lost through injury can only be replaced by differentiation of progenitor cells.

Congestive heart failure

(CHF). A medical condition in which the contractile function of the heart muscle declines, leading to an enlarged heart with dilated chambers, impaired pumping (left ventricular dysfunction), fluid congestion in the lungs, fluid collection in the legs (oedema) and decreased perfusion of tissues. Patients may have low blood pressure, shortness of breath with exercise or when lying flat, and decreased kidney function.

Grades of CHF

The severity of CHF is graded on a clinical scale from I to IV. This scale was established by the New York Heart Association (NYHA). NYHA class I patients are asymptomatic, even with exertion, and class IV patients have significant symptoms even at rest.

Gastrointestinal stromal tumour

(GIST). A rare cancer of the upper gastrointestinal tract (stomach and duodenum) arising from cells of neuroendocrine origin. Most GIST tumours contain activating mutations in KIT or PDGFRα, and so respond to imatinib and sunitinib therapy.

Left ventricular ejection fraction

(LVEF). A measure of the pumping ability of the heart, defined as the percentage change in the volume of the left ventricle (the main chamber of the heart that pumps blood coming from the lungs out to the body) when the ventricle contracts. A normal LVEF is 50–70%. EFs below 50% indicate LV dysfunction.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A mechanism of cell death mediated by antibody binding to a target cell, followed by recognition through Fc receptors on cytotoxic T-lymphocytes or natural killer cells, leading to target cell killing.

Dilated cardiomyopathy

A condition characterized by both dilation of the heart and reduced contractile function, often leading to CHF.

Pressure overload stress

A technique used in experimental animals that leads to a marked and sudden increase in blood pressure in the heart, which is typically induced by partially occluding the aorta with a suture.

Mitochondrial permeability transition pore

A mitochondrial pore that, when opened by pathological stresses, leads to collapse of the mitochondrial membrane potential, disruption of energy production, and mitochondrial swelling and rupture with release of cytochrome c.

Neointima

The intima is the layer of the arterial wall immediately adjacent to endothelial cells. After catheter intervention, a hypercellular intima can re-form, leading to re-obstruction of the vessel.

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Force, T., Krause, D. & Van Etten, R. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7, 332–344 (2007). https://doi.org/10.1038/nrc2106

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