Why do Kinase Inhibitors Cause Cardiotoxicity and What can be Done About It?

Why do Kinase Inhibitors Cause Cardiotoxicity and What can be Done About It?

Progress in Cardiovascular Diseases 53 (2010) 114 – 120 www.onlinepcd.com Why do Kinase Inhibitors Cause Cardiotoxicity and What can be Done About It...

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Progress in Cardiovascular Diseases 53 (2010) 114 – 120 www.onlinepcd.com

Why do Kinase Inhibitors Cause Cardiotoxicity and What can be Done About It? Hui Cheng, Thomas Force⁎ Center for Translational Medicine and Cardiology Division, Thomas Jefferson University, Philadelphia, PA

Abstract

Cancer growth and metastasis are often driven by activating mutations in, or gene amplications of, specific tyrosine or serine/threonine kinases. Kinase inhibitors (KIs) promised to provide targeted therapy—specifically inhibiting the causal or contributory kinases driving tumor progression while leaving function of other kinases intact. These inhibitors are of 2 general classes: (1) monoclonal antibodies that are typically directed against receptor tyrosine kinases or their ligands and (2) small molecules targeting specific kinases. The latter will be the focus of this review. This class of therapeutics has had some remarkable successes, including revolutionizing the treatment of some malignancies (eg, imatinib [Gleevec] in the management of chronic myeloid leukemia) and adding significantly to the management of other difficult to treat cancers (eg, sunitinib [Sutent] and sorafenib [Nexavar] in the management of renal cell carcinoma). But in some instances, cardiotoxicity, often manifest as left ventricular dysfunction and/or heart failure, has ensued after the use of KIs in patients. Herein we will explore the mechanisms underlying the cardiotoxicity of small-molecule KIs, hoping to explain how and why this happens, and will further examine strategies to deal with the problem. (Prog Cardiovasc Dis 2010;53:114-120) © 2010 Elsevier Inc. All rights reserved.

Keywords:

Kinase inhibitors; Cardiotoxicity; Heart failure

Protein kinases and cancer Protein kinases are enzymes that catalyze transfer of a phosphate residue from ATP to tyrosine, serine, or threonine residues in their substrate proteins. This phosphorylation of substrates results in changes in substrate activity, subcellular location, stability, etc. Although the gain-of-function mutations, gene amplifications, and/or overexpression that drive tumorigenesis can occur in a variety of different gene classes, these genes, in many cases, encode protein kinases, typically tyrosine kinases (TKs).1 Approximately 90 of the 518 kinases in the human kinome are TKs.2 Tyrosine kinases play central Statement of Conflict of Interest: see page 119. ⁎ Address reprint requests to: Thomas Force, Center for Translational Medicine, Thomas Jefferson University, College Building, Suite 316, 1025 Walnut St., Philadelphia, PA 19107. E-mail address: [email protected] (T. Force).

0033-0620/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2010.06.006

roles in transducing extracellular signals (ie, growth factors and cytokines) into activation of signaling pathways that regulate cell growth, differentiation, metabolism, migration, apoptosis, etc. Kinases that are mutated or overexpressed in cancers typically activate cellular pathways that lead to promotion of cell cycle entry (proliferation), inhibition of proapoptotic factors, activation of antiapoptotic factors, and/or promotion of angiogenesis. Data from tumor sequencing projects have found remarkable mutation rates in protein kinases. One study found that mutations in as many as 120 kinases (approximately 25% of the kinome) were present in some cancers.3 Furthermore, many of these mutations were not just “bystanders” but were so-called driver mutations (ie, playing a role in tumor progression). Given this complexity, it seems inconceivable that inhibiting individual kinases in cancer would be effective, except for the relatively rare malignancies that are truly “oncogene-addicted” to a specific mutated kinase (eg, chronic myeloid leukemia

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Abbreviations and Acronyms TK = tyrosine kinase KI = kinase inhibitors TKI = tyrosine kinase inhibitors CML = chronic myeloid leukemia

[CML] and Bcr-Abl). Surprisingly, “targeted therapeutics” have radically transformed the treatment of some hematologic malignancies and solid tumors. Kinase inhibitors

GIST = gastrointestinal stromal tumors

The identification of mutated or amplified kinases has allowed the AMPK = AMP-activated development of theraprotein kinase peutics specifically tarVEGFR = vascular endothelial geting the oncogenic growth factor receptor kinases. Although oncogenic mutations comPDGFR = platelet-derived monly occur in other growth factor receptor classes of proteins in PI3K = phosphatidylinositol addition to kinases, 3-kinase such as cell cycle regulators and proapoptotic or antiapoptotic factors, kinases have become favorite targets of the pharmaceutical industry due not only to their importance in tumor initiation and progression but also to the relative ease with which inhibitors can be made (see below). This has led to an explosion in drug development targeting TKs (TK inhibitors) and, to a lesser but increasing extent, serine/ threonine kinases. At present, 12 small-molecule kinase inhibitors (KIs) are Food and Drug Administration (FDA)– approved for cancer therapy (Table 1), with several more seeking approval over the next 2 years7 and many more (N100) in various phases of development. The first KI to LV = left ventricle

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reach market was imatinib in 2001. It is still the most commercially successful KI, with sales close to $4 billion in 2009. Imatinib revolutionized the treatment of CML. Before the introduction of imatinib, CML was uniformly fatal within 5 years, whereas now, ≈90% of patients are alive 5 years after diagnosis. Indeed, this and other drugs have changed our thinking about some cancers that can now be viewed as a group of diseases that, even if not curable, can be managed effectively for years, similar to many other chronic diseases. Mechanisms of action of KIs Small-molecule KIs typically compete with ATP for binding to the ATP pocket of the kinase. If ATP cannot bind, phosphotransferase activity is blocked and downstream substrates cannot be phosphorylated, even if the kinase is fully activated. In the cell, ATP is present in millimolar concentrations, but KIs will be present in nanomolar to very low micromolar concentrations. Thus, the KIs must bind with very high affinity. Because the structure of the ATP pocket is known for many kinases and is highly conserved across the human genome, it is relatively easy to make an inhibitor that blocks the ATP pocket of a kinase of interest. These inhibitors are termed type I inhibitors. Given the degree of conservation, it is not surprising that lack of selectivity is an issue with most type I inhibitors.5 Type II inhibitors (eg, imatinib and the related nilotinib) not only bind the ATP pocket but also interact with a site adjacent to the pocket, generally making them more selective.9 Furthermore, unlike type I inhibitors, which only bind to an active kinase (because the ATP pocket is only accessible when the kinase is activated), type II inhibitors can also bind to the kinase

Table 1 FDA-approved KIs for cancer therapy Targets Agent (Trade Name) Imatinib (Gleevec) Nilotinib (Tasigna) Dasatinib (Sprycel) Sunitinib (Sutent) Sorafenib (Nexavar) Lapatinib (Tykerb) Gefitinib (Iressa) Erlotinib (Tarceva) Pazopanib (Votrient) Temsirolimus (Torisel) Everolimus (Afinitor) Sirolimus (Rapamune)

Primary Bcr-Abl Bcr-Abl and most IRMs Bcr-Abl and most IRMs VEGFRs, PDGFRs, c-Kit Raf-1/B-Raf, VEGFR2, PDGFRβ EGFR (ERBB1), HER2 (ERBB2) EGFR EGFR VEGFR, PDGFR, c-Kit mTOR mTOR mTOR

Other

Representative Malignancies 5,6

Abl, c-Kit, PDGFRs, DDR1, etc Abl, c-Kit, PDGFRs Abl, c-Kit, PDGFRs, DDR1, etc5,6 CSF-1R, FLT3, RET, etc c-Kit, FLT3, etc NI NI NI NI NI NI NI

CML, Ph+ ALL, CMML, HES, GIST Imatinib-resistant CML, ALL, GIST Imatinib-resistant CML, ALL, GIST RCC, GIST RCC, hepatocellular carcinoma HER2+ breast cancer, ovarian cancer, gliomas, NSCLC NSCLC, gliomas NSCLC, pancreatic cancer, gliomas RCC RCC RCC RCC

Abbreviations: IRMs indicates imatinib-resistant Abl mutants; NI, none identified; Ph+ ALL, Philadelphia chromosome–positive acute lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; HES, hypereosinophilic syndrome; NSCLC, non–small-cell lung cancer; CLL, chronic lymphocytic leukemia; RCC, renal cell carcinoma; CSF-1R, colony-stimulating factor 1 receptor; FLT3, FMS-like tyrosine kinase 3; RET, rearranged during transfection; mTOR, mammalian target of rapamycin. Please see text for additional abbreviations.

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when it is in the inactive conformation. Therefore, these agents possess enhanced selectivity and are typically (though not always) more potent. Type III inhibitors (eg, the families of mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors including PD98059 and UO126) bind to regions remote from the ATP pocket. These regions are typically not highly conserved, accounting for the excellent selectivity of the aforementioned mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors.10 Although type III agents are more selective, they are a small minority of agents in development because they are more difficult to design and not as predictably effective. With that said, there is intense interest in these types of compounds, particularly for the treatment of imatinibresistant CML because the mutations leading to resistance are, to date, all in the kinase domain, and therefore, the mutated kinases should still be inhibited by type III agents.

few prospective studies have been performed to carefully examine the issue. Thus, in most cases, the practicing cardiologist and oncologist will not know whether a new agent will be problematic. Furthermore, long-term followup of patients is not available because of the recent introduction of these drugs. As opposed to traditional chemotherapeutics, KIs are often taken for life because withdrawal can lead to reemergence of the malignancy. Thus, long-term follow-up of patients will be particularly important. Furthermore, it must be realized that the typical preapproval trial enrolls the healthiest of the cancer patients, and patients with comorbidities, particularly cardiovascular comorbidities, are usually excluded. Thus, confirmation of lack of toxicity must await approval when the agent will be used in a broader population of cancer patients with cardiovascular comorbidities. This supports the need for patient registries, which allow caregivers and researchers to identify critical problems post-FDA approval.

KIs: a concern for the heart Molecular mechanisms of cardiotoxicity Against the successes in cancer with the smallmolecule inhibitors and the belief that these targeted therapeutics would be far less toxic than traditional chemotherapy, it was something of a surprise when cardiotoxicity was detected. The first report of cardiotoxicity with a small-molecule KI was a case series of 10 patients who developed congestive heart failure while receiving imatinib.11 Subsequently, much more serious toxicity was identified in the first study specifically focused on cardiotoxicity of a small-molecule KI.12 In this study, serial evaluations of left ventricle (LV) ejection fraction and biomarker determinations (troponin I) were performed in patients with gastrointestinal stromal tumors (GISTs) receiving sunitinib. Eighteen percent of patients fully developed either congestive heart failure or a decline in LV ejection fraction of more than 15 percentage points. In addition, cardiotoxicity with sorafenib treatment has also been reported though overall risk is unclear.13 It is critical to note, however, that cardiotoxicity is not a class effect of KIs because the risk of significant cardiotoxicity seems to be low for most of the approved agents. Only those that target essential kinases expressed in the heart and vasculature will likely have associated cardiotoxicity. Currently, small-molecule KIs account for ≈20% of all money spent in drug development and the majority of that (≈80%) is in cancer (with a small percentage in inflammatory and other diseases). There seems to be no slowing down in this important and increasingly lucrative area, and we will likely see many more of these agents on the market over the next several years. However, other than screening for QT prolongation, it is quite rare for these agents to be screened for cardiotoxicity, and very

In 2002, Hoshijima and Chien14 drew largely theoretical parallels between the dysregulation of the signaling pathways driving cancer and those driving cardiac hypertrophy. Indeed, there are numerous parallels between signaling pathways that drive tumorigenesis and those that regulate not only hypertrophy but also survival of cardiomyocytes, especially in the stressed heart. Hence, inhibition of the “key” kinases that drive tumorigenesis could potentially compromise the survival of cardiomyocytes. Indeed, this seems to be at the core of the cardiotoxicity of KIs. The 2 types of toxicity will be discussed here to elucidate the underlying molecular mechanisms of KI-derived cardiotoxicity. On-target toxicity With on-target toxicity (also known as mechanismbased or target-related), the kinase that is targeted in the cancer also provides an important maintenance function in the heart and vasculature (Cheng and Force 7 and references therein). Thus, inhibiting it leads to adverse consequences in the heart. A classic example is the cardiac toxicity caused by trastuzumab (Herceptin), a monoclonal antibody against the ERBB2 receptor (also known as HER2). The HER2 receptor is overexpressed in approximately 20% of breast cancers and is critical for driving progression. Inhibiting HER2 with trastuzumab provides a survival advantage in patients, but LV dysfunction can occur. Although the precise mechanism of trastuzumab cardiotoxicity is still being debated, it is apparent that HER2 plays a critical role in cardiomyocyte proliferation (during development) and survival (during adulthood). In addition, HER2 protects against anthracycline

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cardiotoxicity, probably accounting for the marked increase in LV dysfunction seen when the two were administered together. Trastuzumab-related cardiotoxicity will be discussed by Suter et al in this issue. Imatinibinduced cardiotoxicity is another example of on-target toxicity, mechanisms of which have been extensively reviewed recently.7 Off-target toxicity With off-target toxicity, a kinase that was not intended to be inhibited by a drug is inhibited, and if this kinase plays a key role in the heart, this inhibition will lead to cardiotoxicity. Off-target toxicity is inherently related to the limited selectivity of most KIs (especially type I

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inhibitors) and the size of the human kinome. For example, sunitinib, which was initially developed primarily to inhibit vascular endothelial growth factor receptors (VEGFRs) 13, platelet-derived growth factor receptors (PDGFRs) α/β, and c-Kit, has been predicted to inhibit at least 50 kinases.16 In cultured cardiomyocytes, sunitinib induced loss of mitochondrial membrane potential and energy rundown.17 Typically, when energy stores drop in the cardiomyocyte, a kinase called AMP-activated protein kinase (AMPK) is activated, leading to increased energy generation and decreased energy utilization. However, AMPK was not activated in the energy-stressed cardiomyocytes. In fact, AMPK activity was reduced in hearts of sunitinib-treated mice and cardiomyocytes in culture, and this was due to potent and direct inhibition of AMPK by sunitinib. Thus,

Fig 1. Adverse effects of sunitinib on energy-responsive signaling pathways in the heart. In cultured cardiomyocytes, sunitinib, via unclear mechanisms, induces loss of mitochondrial membrane potential and energy stress (increase in AMP/ATP ratio), which, together with CaMKK- and/or LKB1-mediated phosphorylation of T172 of AMPK, activates AMPK. This produces a number of relatively rapid responses including (1) phosphorylation of ACC1/2 and phosphofructokinase (PFK), leading to decreased fatty acid synthesis, increased fatty acid oxidation, and increased glycolysis, and (2) inhibition of mTORC1 signaling, leading to increased eEF2 phosphorylation (mediated by eEF2Kinase) and inhibition of eEF2.18 This leads to inhibition of protein translation (a major energy-consuming process in cardiomyocytes) and protein synthesis. Together, these responses help to restore energy homeostasis. However, in the presence of sunitinib, ATP cannot bind to AMPK, and therefore, AMPK cannot transfer phosphate from ATP to the substrates. Thus, the energy-conserving mechanisms are not recruited and energy depletion is exacerbated. Although multiple other AMPK-independent inputs, including inhibition of receptor tyrosine kinase (RTK) signaling, can lead to inhibition of mTORC1, inhibition of protein translation via these mechanisms is incomplete and energy rundown continues.

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the findings suggested that off-target inhibition by sunitinib of AMPK, a kinase that plays key roles in maintaining metabolic homeostasis in the heart, especially in the setting of energy stress, accounts, at least in part, for sunitinibinduced toxicity seen in cardiomyocytes. This represented the first example of off-target inhibition of a kinase by a KI leading to cardiotoxicity (Fig 1).17 Selectivity versus multitargeting One obvious question to address is: why not make more selective inhibitors, thereby reducing off-target effects? One reason, noted above, is that ATP competitive inhibitors are relatively easy to make and more predictably effective. The other reason is more complex but important to understand. Tumor growth in most cases is driven by mutations in more than one kinase. The clearest example of this is the necessity of tumor neoangiogenesis for a tumor to grow beyond a certain size. Thus, one clear direction in drug design is “multi-targeting,” in which a single drug targets both VEGF receptors and kinases that specifically drive tumor growth. Examples of this trend are sunitinib and sorafenib, which are approved for several solid tumors and are in development for many more, and although multitargeting can enhance tumor cell killing, the flip side is that this leads to inherent nonselectivity and potential increased risk of cardiac dysfunction. One final note on mechanisms of cardiotoxicity of VEGFR inhibitors is that studies in mouse models have suggested that angiogenesis is key to maintaining cardiac homeostasis in response to pressure overload,19,20 which, taken together with the significant hypertension induced by VEGFR inhibitors, might explain, in part, the LV dysfunction seen with sunitinib. More recently, PDGFRβ, another target of sunitinib, was also found to be critical for angiogenesis, and deletion of the gene in mice led to heart failure when the mice were exposed to high pressure loads.21 A variant of multitargeting is using multiple drugs to target multiple components of a single pathway. This strategy is gaining popularity particularly for targeting the growth factor receptor/PI3K/Akt pathway. Components of this pathway are mutated or overexpressed in a host of cancers, and typically, multiple components are mutated in each tumor, making this pathway an ideal target in cancer therapy.22 Furthermore, Yuan and Cantley23 proposed that redundant activation of the PI3K pathway by multiple mutations or amplifications of pathway components, combined with activation of multiple nonoverlapping pathways will, with the exception of the rare oncogeneaddicted cancer, require combination therapy. The cautionary note here is that this pathway is critical to cardiomyocyte survival in the setting of stress, in insulin sensitivity, and in physiologic growth (driven by p110α).24,25 Inhibition of one or two components of the pathway might allow for sufficient residual signaling down the pathway to preserve cardiomyocyte integrity, yet inhibiting multiple components could

shut down signaling more completely, jeopardizing the cardiomyocyte. Again, hypertension might be a significant exacerbating factor for cardiac dysfunction when components of the PI3K pathway are targeted.25 Heart failure with KIs: cardiomyocyte loss and/or dysfunction? Although it has been possible to implicate critical kinases in KI-induced cardiotoxicity, it remains unclear whether LV dysfunction with KIs is attributable to myocyte loss (and therefore largely irreversible) or myocyte dysfunction (potentially reversible). Neurons and cardiomyocytes seem to be quite resistant to apoptosis induced by cytochrome c release and caspase activation. Contributing to this is the decreased expression of Apaf1 that is directly linked to the tight regulation of caspase activation by endogenous XIAP.26 Consistent with this, we did not see an increase in apoptosis in mice treated with sunitinib until we exposed the mice to phenylephrine-induced pressure load, and even then the increase in cell death was modest.12 In contrast, we saw clear evidence of opening of the mitochondrial permeability transition pore in the mice as evidenced by marked mitochondrial swelling and destruction of the normal mitochondrial architecture.12 Strikingly, we saw a very similar picture in transmission electron micrographs of an endomyocardial biopsy obtained from a patient who presented with advanced heart failure while receiving sunitinib.12,17 This picture could be consistent with LV dysfunction being secondary to impaired energy generation, with or without cell death by necrosis. Furthermore, sunitinib-induced LV dysfunction can normalize after withdrawal of the drug and/or institution of standard heart failure therapy,12 but this is not a universal response.27 However, whether any reversibility of LV dysfunction is accompanied by reversibility of injuries at the myocyte level, and whether it will be long-lasting, remains unclear. That said, in the patient noted above, there was very striking reversibility at the myocyte level with marked restoration of mitochondrial number and integrity after withdrawal of sunitinib.12,17

Three drug development approaches to dealing with toxicity (1) Obtain the complete kinase selectivity profile of a drug and use that to predict cardiotoxicity Given the fact that a nonselective agent may have better anticancer activity and can be used in more cancers, it seems safe to say that for the near future, we will be forced to identify mechanisms of cardiotoxicity of relatively nonselective drugs. This will make it essential to know the full-

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selectivity profile of any agent against the entire kinome to be able to define mechanisms of toxicity. At present, available commercial platforms for kinase selectivity profiling typically cover approximately half of the kinome (250-300 kinases; eg, www.millipore.com, www. proqinase.com). KINOMEscan (a division of Ambit Biosciences, http://www.ambitbio.com/technology/) has recently developed a high-throughput, active site-dependent competition-binding assay platform that provides scientists with access to a broader panel of 442 kinase assays. Thus, with the advancement of profiling technologies, lack of a full-selectivity profile is a deficit that should be corrected shortly. Based on the full kinase selectivity profile of a KI, we will, in some cases, be able to predict toxicities of drugs. Added to this, many kinases are simply not expressed in the heart, and although they may lead to other organ toxicities, the heart should be spared. The glaring limitation of this “best guess” approach is that we simply do not know the roles played by many kinases that are expressed in the heart and may be targets of KIs. Although prior studies in various models have identified key roles that some kinases play in the heart and vasculature,7 much more work needs to be done to understand the roles of those novel kinase targets. Predicting problematic agents based on studies with gene-targeted mice can give valuable information, especially when combined with pathway analysis programs such as Jubilant (http://www.jubilantbiosys.com), ToxWiz (http://www.camcellnet.com), and Ingenuity (http://www. ingenuity.com). As a caveat, because drugs never inhibit their targets 100%, knockouts would likely have more severe phenotypes than any drug targeting the kinase of interest. With those caveats in mind, we refer the reader to recent reviews examining how mouse models can predict cardiotoxicity.7,28 (2) Redesign a drug to avoid the cardiotoxicity If one can identify the mechanisms of cardiotoxicity of a specific KI, the compound could be redesigned to avoid the target. For example, Kerkela et al11 determined that imatinib-mediated cardiotoxicity was due to the inhibition of c-Abl in the cardiomyocyte, resulting in endoplasmic reticulum stress and cell death. Motivated by this finding, Fernandez et al29 and Demetri30 redesigned imatinib to no longer inhibit Abl (but still inhibited c-Kit), and cardiotoxicity was significantly reduced. Although the redesigned drug was obviously ineffective in treating CML (driven by Bcr-Abl), it was equally effective to imatinib in treating GIST models driven by c-Kit mutations. Thus, by knowing the mechanism of toxicity and redesigning the drug accordingly, one could theoretically reduce cardiotoxicity. Other examples of this strategy can be found in recent reports by Crespo et al31 and Fernandez et al.32 If proved to be effective, this

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redesign strategy would potentially curb cardiotoxicities caused by multitargeted drugs and enhance their safety. (3) Targeted delivery of drugs specifically to cancer cells Compared with the traditional drug delivery systems, targeted delivery seeks to concentrate the agent in the tissue of interest (eg, malignant tumors), while reducing the relative concentration of the drug in other tissues. This improves drug efficacy while minimizing the adverse effects and thus has been proposed to deal with the unavoidable on-target toxicities of cancer drugs. During the last two decades, nanotechnology strategies have developed a number of targeted nanoparticle delivery systems for cancer therapy, including those against the most difficult challenges such of drug resistance and metastasis.33 Several liposomal, polymer-drug conjugates, and micellar formulations are in the clinic, and an even greater number of nanoparticle platforms are in preclinical development. In a recent study, nanoparticle-mediated delivery of a selective mitogen-activated protein kinase inhibitor was shown to optimize cancer chemotherapy.34 Interestingly, nanoparticles loaded with a PI3K inhibitor demonstrated efficacy in inhibiting tumor angiogenesis in a zebrafish tumor model.35 Thus, targeted delivery of KIs with nanoparticles offers an attractive strategy to tackle the issue of cardiotoxicity. Concluding remarks Currently, preclinical testing is unable to accurately identify agents that will have associated cardiotoxicity. Full-selectivity profiles of agents, coupled with a better understanding of the role played by kinases in the cardiomyocyte, and better preclinical models to detect cardiotoxicity are needed. It is critical for basic cardiovascular researchers and clinicians to understand these agents, their mechanisms of action (including mechanisms by which they kill cancer cells), and how these actions can lead to cardiotoxicity. We believe that with (1) greater awareness of the problem, (2) advances in drug design and delivery, (3) better preclinical screening approaches, and (4) close cooperation among clinical and basic cardiologists, oncologists, and the pharmaceutical industry in the early phases of drug development, cardiotoxicity of cancer therapeutics will become a very manageable problem. Statement of Conflict of Interest All authors declare that there are no conflicts of interest. References 1. Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353:172-187.

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