br result of coronary vasospasm and possibly also
result of coronary vasospasm, and possibly also induce acute myocardial infarction and arrhythmias. Cardiotoxicity from antimetabolites in-volves also ROS formation, mitochondrial dysfunction, lipid peroxida-tion and DNA damage . Organic nitrates can be used to prevent vasospasm in 5-fluorouracil-treated patients .
3.3. Molecular therapies targeting signal transduction
Molecularly targeted therapies interfere with aberrant signaling pathways in the cancer cell or its microenvironment. Single- and multi-kinase inhibitors are selected by their pharmacokinetics and se-lectivity and by cancer entity/stage . Their cardiotoxic effects result from inhibition of kinase signaling in the vasculature and in the heart. However, their exact cardiotoxic mechanisms are incompletely under-stood, and methods to predict their cardiotoxicity are currently being evaluated .
Several inhibitors of tyrosine kinases involved in VEGF signaling have received approval from regulatory agencies (Supplementary Table 1). These tyrosine kinases regulate angiogenesis, vascular and myocardial function and metabolism. Adverse cardiovascular events from these inhibitors are related to their interaction with these cellular functions. Short-term inhibition of tyrosine kinases exacerbates injury from ischemia/reperfusion . Chronic inhibition of VEGF signaling impairs angiogenesis .
Many of the effects of targeted therapies have been related to an in-hibition of VEGF receptors and VEGF-related NO downstream signaling in the cardiovascular system. eNOS-phosphorylation and reduced activ-ity go along with increased vascular ROS levels . This contributes to endothelial dysfunction, microvascular injury, vascular stiffness, and fi-nally hypertension . Likewise, VEGF inhibitors may promote throm-bosis, eventually resulting in venous and arterial thromboembolic events . Small molecule TKI inhibits several kinases in parallel. It is currently unclear why individual patients respond to TKI medication with cardiotoxicity. To that effect, cell culture models are being tested to identify a patient's individual susceptibility . Finally, TKI-associated inhibition of the platelet derived growth factor receptor (PDGFR) may further explain the development of ALLN failure in this group of tumor therapeuticals, given that mice lacking PDGFR develop heart failure .
Current evidence for cardiotoxicity has been derived from secondary outcomes of studies in cancer patients. The precise nature of adverse events, their frequency, and their potential impact on patient manage-ment have recently been summarized . The most frequent cardio-vascular adverse events include arterial hypertension and arrhythmia (QTc prolongation) . The risk for myocardial ischemia and stroke is increased up to 2-fold, and there is a trend towards increased arterial and venous thrombotic events. Currently, no guideline recommenda-tion exists for anticoagulation in these patients. The topic of thrombosis
vs. anticoagulation is particularly difficult as VEGF targeted therapies also carry a relevant risk for bleeding [66,68], therefore requiring indi-vidual decision making in case either event occurs.
Emerging evidence also points to increased risk of heart failure from VEGF-targeting therapy. The primary recommendation for cancer pa-tients treated with anti-angiogenic agents is therefore to control for car-diovascular risk factors. The efficacy of preventive measures still remains to be evaluated . Tyrosine kinase inhibitors targeting endo-thelial growth factor receptor (EGFR, e.g. erlotinib in non-small cell lung cancer) may contribute to the development of hypertension, but appear to have less cardiotoxicity [58,59].
Another novel class of targeted therapies is serine-threonine protein kinase inhibitors (e.g. the BRAF [mutated rapidly accelerated fibrosar-coma kinase B] inhibitors dabrafenib and vemurafenib, and the MEK [mitogen-activated protein kinase kinase] inhibitors trametinib and cobimetinib). These agents have individually and in combination im-proved survival in patients with metastatic melanoma. In 40% of all mel-anoma patients, somatic BRAFV600 mutations indicate a targetable oncogenic dependency . Treatment-associated complications with BRAF and MEK inhibitors occur particularly with combination therapies . Adverse cardiovascular events have been related to protein kinase inhibition in cardiomyocytes, e.g. QTc prolongation with dabrafenib and heart failure with trametinib.
BRAF/MEK inhibitors target a central signaling pathway with multi-ple targets and functions . A final signaling step is ERK which in turn targets N100 substrates involved e.g. in cardiac metabolism and growth [72,73]. The toxic effects of BRAF/MEK inhibitors and their downstream events have not been analyzed yet in great detail in preclinical studies. Exact metrics of incidence of such toxicities from long-term studies are missing. The efficacy of established heart failure therapies, including ACE inhibitors and β blockers in this specific situation, remains to be evaluated.