Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes

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.

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

“…Constitutive activation of tyrosine kinase (TK) signaling, via either gain-of-function (GOF) mutations or overexpression due to gene amplification, is found in about 70% of malignancies (Blume-Jensen and Hunter, 2001;Chen et al, 2008). Well-understood examples include overexpression of ERBB2 in HER2 + breast cancer (Force et al, 2007) and the constitutively active oncogenic fusion protein BCR-ABL, which can cause CML (Force et al, 2007;Chen et al, 2008;Force and Kolaja, 2011). This dependency of tumor formation and proliferation on TK signaling led to the rise of TKIs as promising anti-cancer therapeutics.…”

“…Currently, there are two chemical classes of TKIs: (1) humanized monoclonal antibodies (mAbs) and (2) small molecule inhibitors (Force et al, 2007;Chen et al, 2008;Force and Kolaja, 2011). Small molecule TKIs can be further subcategorized based on whether they compete with ATP for the binding pocket or interact with other regions of the protein (Force and Kolaja, 2011).…”

“…Reported cardiotoxicities include heart failure, cardiomyopathy, conduction abnormalities, QT prolongation, and myocardial injury. The most common toxicity is systolic dysfunction or cardiomyopathy, potentially leading to heart failure, which is most likely mediated through direct toxicity of cardiomyocytes (Albini et al, 2010;Eschenhagen et al, 2011;Force and Kolaja, 2011;Raschi and De Ponti, 2012;Ewer and Ewer, 2015).…”

“…Investigations of these adverse events revealed that many of the tyrosine kinases targeted by TKIs serve critical roles in survival and maintenance of cardiomyocytes, leading to unintended on-target toxicity. At the same time, many TKIs inhibit multiple kinases simultaneously, which can cause off-target toxicity (Chen et al, 2008;Force and Kerkelä, 2008;Force and Kolaja, 2011).…”

“…Despite the risk of cardiotoxicity, TKIs are still one of the highly effective and favored cancer therapeutics on the market (Eschenhagen et al, 2011;Force and Kolaja, 2011). The success of drugs such as trastuzumab and imatinib, a small molecule inhibitor used to treat chronic myeloid leukemia (CML), has inspired the development of additional TKIs.…”