Abstract
Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.
Highlights
Sunitinib Malate (Sutent1) is a small molecule tyrosine kinase inhibitor (TKI) clinically approved to treat gastrointestinal stromal tumors, metastatic renal cell carcinoma and pancreatic neuroendocrine cancers [1] and is currently being implemented in over 130 trials across diverse cancer indications [2]
Our findings suggest that a cardiac positron emission tomography (PET) strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment
The burgeoning field of cardio-oncology is driven by cardiovascular complications that occur as a direct result of cancer treatments
Summary
Sunitinib Malate (Sutent1) is a small molecule tyrosine kinase inhibitor (TKI) clinically approved to treat gastrointestinal stromal tumors, metastatic renal cell carcinoma and pancreatic neuroendocrine cancers [1] and is currently being implemented in over 130 trials across diverse cancer indications [2]. Sunitinib is thought to exert multiple effects on tumor growth, survival and angiogenesis. A significant toxicity profile has been reported [5]. It is strongly contended that there has been a significant and widespread under-recognition of sunitinib cardiotoxicity [6]. The long term impact of sunitinib treatment on cardiovascular function is still largely unknown, with no widespread structured protocols, guidelines or follow-up programs focusing on cardiovascular care and survivorship-related issues in place [10]
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