Sunitinib-Induced Cardiotoxicity Is Mediated by Off-Target Inhibition of AMP-Activated Protein Kinase

Kerkelä, Risto; Woulfe, Kathleen C.; Durand, Jean-Bernard; Vagnozzi, Ronald J.; Krämer, David Kitz; Chu, Tammy F.; Beahm, Cara; Chen, Ming Hui; Force, Thomas

doi:10.1111/j.1752-8062.2009.00090.x

Cited by 23 publications

(40 citation statements)

References 36 publications

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“…Other mechanisms by which multi-kinase inhibition can produce cardiotoxicity have been described (35). For example, sunitinib inhibits adenosine monophosphate (AMP)-activated protein kinase (AMPK), which plays a key role as a master regulator of cellular energy homeostasis, resulting in damage to cardiomyocytes (36). We confirmed that sunitinib inhibited kinase activity of AMPK-alpha with an IC 50 value of 0.061 mmol/L and that sunitinib suppressed cellular phosphorylation and activity of AMPK-alpha in rat cardiomyocytes at 1 mmol/L (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Fujita

Miyadera

Kato

et al. 2013

Molecular Cancer Therapeutics

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VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signaltargeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI 50 > 10 mmol/L) in VEGFR signal-or MET signalindependent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685-96. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Fujita

Miyadera

Kato

et al. 2013

Molecular Cancer Therapeutics

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“…With the wider usage in clinical practice, side-effects of sorafenib began to be recognized and some of which may be potentially life threatening, such as congestive heart failure (CHF), arterial thrombosis, wound dehiscence, haemorrhage, hypertension, and renal dysfunction (Chu et al, 2008;Wu et al, 2008;Chu et al, 2009;Je et al, 2009;Kerkela et al, 2009;Choueiri et al, 2010;Ewer et al, 2010;Hutson et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Risk of Treatment-related Mortality with Sorafenib in Patients with Cancer

Zhang

Zhang²,

Yu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. Methods: Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. Results: 13 trials recruiting 5,546 patients were included in our analysis.

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“…Particularly, the cardiovascular function is likely to be affected by TKI effects on VEGF and its receptors, as VEGF signaling has an important role in regulating myocardial responses to hemodynamic forces, such as pressure overload, and also on physiological and pathological changes in cardiomyocytes (6). Off-target effects of these drugs might also induce cardiomyocyte toxicity due to TKI non-selectivity (7,8). Indeed, virtually, all TKIs have been associated with cardiovascular events (9).…”

Section: Discussionmentioning

confidence: 99%

Toxic cardiomyopathy leading to fatal acute cardiac failure related to vandetanib: a case report with histopathological analysis

Scheffel

Dora

Siqueira

et al. 2013

European Journal of Endocrinology

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Context: Medullary thyroid carcinoma (MTC) accounts for 3-4% of all malignant thyroid neoplasias. Vandetanib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor 2, epidermal growth factor receptor, and RET, has been approved by the FDA for the treatment of locally advanced or metastatic MTC. The heart seems to be particularly susceptible to adverse effects associated with TKI therapy, and virtually all TKIs have been associated with cardiovascular events. Clinical presentation: We report the case of a patient with metastatic MTC who was enrolled in the Phase III clinical study (NCT00410761) and presented a favorable response to vandetanib therapy, displaying marked decrease in the level of serologic tumor markers and shrinkage of metastatic lesions. After 14 months of therapy, the patient developed a fatal cardiac failure. Myocardial infarction was excluded by serial measurements of specific cardiac markers (serial troponin-T measurements varied from 0.037 to 0.042 ng/ml) and serologic tests for Chaga's disease were negative. Postmortem examination of the heart revealed cardiomyocyte hypertrophy and marked myocyte degeneration in the subendocardial zones and papillary muscles of the myocardium. These pathological changes are similar to those observed in TKI-treated rats and are suggestive of drug-induced cardiotoxicity. Conclusion: This case illustrates a previously unreported serious vandetanib-related adverse effect and highlights the need for close monitoring of patients under TKI therapy in order to identify early signs of congestive heart failure or myocardium damage.

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Sunitinib-Induced Cardiotoxicity Is Mediated by Off-Target Inhibition of AMP-Activated Protein Kinase

Cited by 23 publications

References 36 publications

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Risk of Treatment-related Mortality with Sorafenib in Patients with Cancer

Toxic cardiomyopathy leading to fatal acute cardiac failure related to vandetanib: a case report with histopathological analysis

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