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  • Review Article
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Targeting non-malignant disorders with tyrosine kinase inhibitors

Nature Reviews Drug Discovery volume 9, pages 956–970 (2010)Cite this article

Subjects

Key Points

  • Receptor and non-receptor tyrosine kinases are involved in multiple proliferative signalling pathways.

  • Imatinib, one of the first tyrosine kinase inhibitors (TKIs) to be approved, revolutionized the treatment of chronic myelogenous leukaemia. Other compounds with different spectra of kinase inhibition are currently used to treat renal cell carcinoma, non-small-cell lung cancer and colon cancer.

  • More recently, the therapeutic potential of TKIs in non-malignant disorders has been recognized.

  • Clinical research has progressed far in pulmonary vascular disorders: imatinib has already undergone a randomized, placebo-controlled Phase II trial, in which it had good safety and tolerability, and provided substantial haemodynamic improvement. A Phase III trial of this compound in pulmonary arterial hypertension is ongoing.

  • In addition, recent preclinical reports support the potential use of TKIs as anti-proliferative agents in non-malignant disorders such as cardiac hypertrophy, lung fibrosis, rheumatoid disorders, atherosclerosis, in-stent restenosis, glomerulonephritis and arthritis.

  • In addition to questions of selectivity and non-selectivity, aspects of safety and long-term administration of tyrosine kinase inhibitors in non-malignant indications require careful consideration.

Abstract

Receptor and non-receptor tyrosine kinases are involved in multiple proliferative signalling pathways. Imatinib, one of the first tyrosine kinase inhibitors (TKIs) to be approved, revolutionized the treatment of chronic myelogenous leukaemia, and other TKIs with different spectra of kinase inhibition are used to treat renal cell carcinoma, non-small-cell lung cancer and colon cancer. Studies also support the potential use of TKIs as anti-proliferative agents in non-malignant disorders such as cardiac hypertrophy, and in benign-proliferative disorders including pulmonary hypertension, lung fibrosis, rheumatoid disorders, atherosclerosis, in-stent restenosis and glomerulonephritis. In this Review, we provide an overview of the most recent developments — both experimental as well as clinical — regarding the therapeutic potential of TKIs in non-malignant disorders.

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Figure 1: General signalling pathways of receptor tyrosine kinases in cancer.
Figure 2: Comparison of receptor tyrosine kinase signalling in cardiomyocytes, smooth muscle cells and myofibroblasts.
Figure 3: Timeline breakthrough discoveries in RTK signal transduction in health and disease (cancerous and non-malignant).

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Authors and Affiliations

  1. University Hospital Giessen and Marburg, Medical Clinic II/IV/V, Klinikstrasse 36, 35398, Giessen, Germany

    Friedrich Grimminger & Hossein A. Ghofrani

  2. University of Giessen Lung Center, Aulweg 130, 35398, Giessen, Germany

    Friedrich Grimminger, Ralph T. Schermuly & Hossein A. Ghofrani

  3. Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231, Bad Nauheim, Germany

    Ralph T. Schermuly

Authors
  1. Friedrich Grimminger
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  2. Ralph T. Schermuly
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  3. Hossein A. Ghofrani
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Correspondence to Hossein A. Ghofrani.

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Competing interests

All authors have received financial support from non-commercial sources — namely, grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the German Ministry for Education and Research. All authors have financial relationships with commercial sources, including consultancies at Bayer HealthCare, Pfizer and Novartis; board or advisory board membership at Bayer HealthCare, Pfizer, GlaxoSmithKline (GSK) and Novartis; and honoraria from Bayer HealthCare, GSK, Pfizer, and Novartis. All authors have industry-sponsored grants from Bayer HealthCare, Pfizer and Novartis.

Glossary

Fibrosis

The pathological formation of fibrous connective tissue as a repair response (for example, wound healing) or a separate active process that affects the normal architecture of the underlying organ or tissue (for example, lung fibrosis and heart fibrosis).

Right ventricular pressure

The pressure in the ventricular heart chamber on the right side, which also reflects the systolic blood pressure in the pulmonary artery and can be assessed non-invasively by echocardiography or invasively by right heart catheterization.

Cardiotoxicity

The occurrence of disturbances in heart electrophysiology and/or muscle damage resulting in cardiomyocyte dysfunction or death.

Decompensated

Describes the functional deterioration of a previously working structure or system. In the context of heart function, it refers to the progressive decline in the contractility of the myocardium, which can ultimately lead to death from cardiac failure.

Vascular resistance

The force that blood must overcome to maintain perfusion of the blood vessel, calculated as the ratio between pressure and flow.

Vascular remodelling

Structural changes of the vascular wall characterized by intimal, medial and adventitial thickening in response to hypoxia, inflammation, haemodynamic changes or vascular diseases.

Epithelial-to-mesenchymal transition

The trans-differentiation of epithelial cells to mesenchymal cells, characterized by loss of cell adhesion, repression of E cadherin expression and increased cell mobility. It can occur during normal development, as a repair mechanism, or as a mechanism of disease.

Plexiform lesion

A histological hallmark of idiopathic pulmonary arterial hypertension and related conditions. It is a distal pulmonary vascular structure that resembles kidney glomerulae, and its function is not well understood.

Last value carried forward analysis

A method to analyse outcome measures at a given time point even if patients have dropped out of the observation prematurely, whereby the parameter that was last observed is carried forward to the end-point analysis.

paO2

The partial pressure of oxygen in arterial blood. In medicine, it reflects the gas exchange efficiency of the cardiopulmonary system.

Event rate

The number of predefined events occurring in the treatment group (usually in comparison to the corresponding rate in a control group) in clinical trials. The difference in event rate between both groups determines the therapeutic effect and/or the risk to patients.

Cyclosporin A

A calcineurin inhibitor used as a standard immunosuppressive agent for the prevention of graft rejection in transplant medicine.

American College of Rheumatology 70 response

An American College of Rheumatology 70 (ACR 70) response requires a patient to have a 70% reduction in the number of swollen and tender joints, and a reduction of 70% in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in health assessment questionnaire score.

Active rheumatoid arthritis

A chronic, systemic inflammatory disorder that primarily affects synovial joints but may induce diffuse inflammation in the lungs, pericardium, pleura and skin.

Right ventricular hypertrophy

The thickening of the right ventricular myocardium in response to increased afterload, mostly due to pulmonary hypertension.

Left ventricular hypertrophy

The thickening of the left ventricular myocardium that occurs either physiologically in response to exercise or as a pathological reaction to increased afterload (for example, in aortic stenosis, aortic insufficiency and systemic hypertension) or hypertrophic cardiomyopathies.

Tunica media

The middle layer of an artery or vein that is made up of smooth muscle cells and elastic tissue. It is localized between the tunica intima and tunica adventitia.

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Grimminger, F., Schermuly, R. & Ghofrani, H. Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev Drug Discov 9, 956–970 (2010). https://doi.org/10.1038/nrd3297

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