Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes

Doherty, Kimberly; Wappel, Robert L.; Talbert, Dominique R.; Trusk, Patricia B.; Moran, Diarmuid M.; Kramer, James; Brown, Arthur M.; Shell, Scott A.; Bacus, Sarah

doi:10.1016/j.taap.2013.04.027

Cited by 151 publications

(130 citation statements)

References 34 publications

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“…Consequently, it is possible that the in vivo concentration of erlotinib is so high that it may trigger myocardial cell death, resulting in myocardial infarction in addition to tumor cell apoptosis. Additionally, Doherty et al (10) demonstrated that erlotinib marginally reduced lipid deposition of human cardiac cells. Notably, coronary plaque deposition was observed in the patient of the present study; thus, we hypothesize that erlotinib may cause plaque instability, subsequently leading to acute myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

“…EGFR is found on the surface of cancer cells, but is also present on various kinds of normal cells. Doherty et al (10) investigated the toxicity of crizotinib, sunitinib, erlotinib and nilotinib in vitro and revealed that treatment with 10 µM erlotinib caused human cardiomyocyte cell death. It was also demonstrated in a phase I study that the steady-state plasma concentration of erlotinib (150 mg, administered daily) is 1.37-1.64 µg/ml (11).…”

Section: Discussionmentioning

confidence: 99%

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Acute myocardial infarction following erlotinib treatment for NSCLC: A case report

2016

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Abstract. Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is an oral targeted anticancer drug that is used to treat non-small cell lung cancer (NSCLC). Previous studies have confirmed that erlotinib is safe and is well-tolerated by patients. The most common adverse reactions observed following erlotinib treatment include a rash and mild diarrhea. In the current study, the first case of acute myocardial infarction following one month of treatment with erlotinib in a 63-year-old male NSCLC patient is presented. The present study highlights the importance of clinicians remaining cautious following erlotinib administration. In elderly NSCLC patients and those with a history of coronary heart disease, cardiac function must be carefully monitored following erlotinib treatment so that serious adverse reactions, such as myocardial infarction, may be identified early and treated quickly.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Acute myocardial infarction following erlotinib treatment for NSCLC: A case report

2016

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“…EGFR) and does not present the ‘off-target' toxicity of multitargeted TKI [8]. By inhibiting the same pathway as cardiomyocytes [9], long-term erlotinib induced ‘on-target' cardiac toxicity in rats, which has not been confirmed by other studies [10].…”

Section: Discussionmentioning

confidence: 99%

Maintenance Treatment by Erlotinib and Toxic Cardiomyopathy: A Case Report

et al. 2016

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Erlotinib maintenance treatment improves progression-free survival compared with observation after first-line chemotherapy in unselected advanced non-small cell lung cancer (NSCLC). Very few cardiac adverse effects have been observed in phase III studies on tyrosine kinase inhibitors (TKI). We report the case of a 71-year-old woman with metastatic NSCLC treated with cisplatin/pemetrexed and then erlotinib maintenance therapy. After 26 months of TKI therapy, she developed dilated cardiomyopathy. Despite symptomatic treatment, left ventricular ejection fraction decreased to 25%. Ischemic heart disease was excluded by coronary angiography and cardiac magnetic resonance imaging, and no other cause was found. Erlotinib was stopped, and cardiac resynchronization therapy by pacemaker was initiated. This case report highlights the possible cardiotoxic effects of long-term erlotinib and suggests the need for close clinical and echocardiographic follow-up of patients receiving long-term TKI therapy.

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“…TKIs that are known to block the most relevant K + channel (K v 11.1), encoded by the gene traditionally known as hERG (subsequently renamed KCNH2), include crizotinib, sunitinib, and nilotinib. These drugs have been shown to block the channel in vitro and to prolong action potentials in human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) (Doherty et al, 2013). Indirect reductions in K + current may possibly be mediated by Src, a tyrosine kinase that can augment current carried by K v 11.1 (Schlichter et al, 2014).…”

Section: Excitation and Contractionmentioning

confidence: 99%

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

Shim

2018

Biophysical Journal

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Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation-contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP) models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.

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Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes

Cited by 151 publications

References 34 publications

Acute myocardial infarction following erlotinib treatment for NSCLC: A case report

Acute myocardial infarction following erlotinib treatment for NSCLC: A case report

Maintenance Treatment by Erlotinib and Toxic Cardiomyopathy: A Case Report

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

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