Mechanisms of Cardiac Dysfunction Associated With Tyrosine Kinase Inhibitor Cancer Therapeutics

Abstract

HomeCirculationVol. 118, No. 1Mechanisms of Cardiac Dysfunction Associated With Tyrosine Kinase Inhibitor Cancer Therapeutics Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMechanisms of Cardiac Dysfunction Associated With Tyrosine Kinase Inhibitor Cancer Therapeutics Ming Hui Chen, MD, MMSc, Risto Kerkelä, MD, PhD and Thomas Force, MD Ming Hui ChenMing Hui Chen From the Cardiology Department, Children’s Hospital Boston, Boston, Mass (M.H.C.); Department of Medicine, Divisions of Cardiology and Women’s Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.H.C.); Center for Translational Medicine and Cardiology Division, Jefferson Medical College, Philadelphia, Pa (R.K., T.F.); and Program in Cell and Developmental Biology, Jefferson College of Graduate Studies, Philadelphia, Pa (T.F.). Search for more papers by this author , Risto KerkeläRisto Kerkelä From the Cardiology Department, Children’s Hospital Boston, Boston, Mass (M.H.C.); Department of Medicine, Divisions of Cardiology and Women’s Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.H.C.); Center for Translational Medicine and Cardiology Division, Jefferson Medical College, Philadelphia, Pa (R.K., T.F.); and Program in Cell and Developmental Biology, Jefferson College of Graduate Studies, Philadelphia, Pa (T.F.). Search for more papers by this author and Thomas ForceThomas Force From the Cardiology Department, Children’s Hospital Boston, Boston, Mass (M.H.C.); Department of Medicine, Divisions of Cardiology and Women’s Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.H.C.); Center for Translational Medicine and Cardiology Division, Jefferson Medical College, Philadelphia, Pa (R.K., T.F.); and Program in Cell and Developmental Biology, Jefferson College of Graduate Studies, Philadelphia, Pa (T.F.). Search for more papers by this author Originally published1 Jul 2008https://doi.org/10.1161/CIRCULATIONAHA.108.776831Circulation. 2008;118:84–95Treatment of patients with cancer has changed radically over the last several years with the advent of “targeted therapeutics.” Whereas traditional chemotherapy was directed at all rapidly dividing cells, whether cancerous or not, today’s anticancer drugs are increasingly tailored to the specific genetics of each cancer. This targeted approach, predominantly via inhibition of tyrosine kinase activity, has markedly improved the management of cancers including chronic myeloid leukemia (CML), breast cancer, gastrointestinal stromal tumor (GIST), renal cell carcinoma (RCC), and colon carcinoma.1–5Inhibitors of tyrosine kinases are of 2 classes: monoclonal antibodies (mAbs), typically targeting growth factor receptor tyrosine kinases, and small molecules, referred to as tyrosine kinase inhibitors (TKIs), targeting both receptor and nonreceptor tyrosine kinases. The goal of targeted therapy is to improve antitumor activity with fewer toxic side effects than traditional anticancer therapies; given the initial success of this approach, the number of targeted therapy drugs entering into development in the last 5 years has increased dramatically.6,7 However, several recent studies have revealed unanticipated side effects of targeted therapy, including left ventricular (LV) dysfunction and heart failure, the primary manifestations of cardiotoxicity we will be examining here.5,8,9Herein, we will examine the potential risk of LV dysfunction of targeted therapy and the molecular mechanisms that underlie that risk. We will review the importance of tyrosine kinase signaling pathways both for oncogenesis and for the survival of normal cardiomyocytes. To understand basic mechanisms of cardiomyopathy of TKIs, it is critical to understand 2 general classes of toxicity. The first is “on-target” toxicity, wherein the tyrosine kinase target regulating cancer cell survival and/or proliferation (and therefore a good target in cancer therapy) also serves an important role in normal cardiomyocyte survival, and thus inhibition leads to myocardial dysfunction. “Off-target” toxicity occurs when a TKI leads to toxicity via inhibition of a kinase not intended to be a target of the drug. This type of toxicity is intrinsically related to 2 issues: (1) the inherent nonselectivity of TKIs and (2) a trend toward “multitargeting” or purposefully designing drugs to inhibit a broad range of targets that include kinases regulating both tumorigenesis and tumor angiogenesis. Although multitargeting may broaden efficacy of an anticancer agent, likelihood of toxicity would also increase.With the growing number of Food and Drug Administration (FDA)–approved agents and many more in development,6,7 some of these will inhibit novel kinase targets for which little or no clinical data exist on risk of heart failure or LV dysfunction. Therefore, we will also review basic science studies that raise concerns over the potential risk of LV dysfunction in patients treated with drugs that inhibit these kinases. Finally, we will discuss cardiovascular considerations for development of future targeted therapy that may maximize antitumor effects while minimizing cardiac effects in patients being treated with these potentially life-saving medications.Tyrosine Kinases in Signal TransductionResponse to extracellular and intracellular stimuli is vital for all complex living organisms. Activation of signal transduction cascades allows a relatively small stimulus to be amplified into a larger biological response, such as the reprogramming of gene expression.10 Tyrosine kinases, of which there are ≈90 in the human genome,11 play central roles in transducing extracellular signals (ie, growth factors and cytokines) into activation of signaling pathways that regulate cell growth, differentiation, metabolism, migration, and programmed cell death (apoptosis). Tyrosine kinases are families of enzymes that catalyze transfer of a phosphate residue from ATP to tyrosine residues in other proteins (substrates). Phosphorylation can change factors such as the activity, subcellular location, and stability of the phosphorylated substrate protein.There are 2 major classes of tyrosine kinases. Receptor tyrosine kinases (RTKs) are embedded in the cell membrane with an extracellular ligand-binding domain and an intracellular kinase domain that signals to the interior of the cell. In contrast, nonreceptor tyrosine kinases (NRTKs) are located within the cell. By their location, tyrosine kinases can mediate transduction of both extracellular and intracellular signals. Because of their critical role in normal cellular communication and maintenance of homeostasis, tyrosine kinase activity is tightly regulated.10 Tyrosine kinases are normally quiescent until activated by extracellular stimuli or ligands, such as growth factors (eg, vascular endothelial growth factor [VEGF] and platelet-derived growth factor [PDGF]) or intracellular stimuli (such as oxidant stress, activating NRTKs). An exquisite balance between activity of tyrosine kinases and of tyrosine phosphatases, which mediate dephosphorylation of tyrosine residues and therefore act in opposition to kinases, controls the timing and duration of cell signaling.Abnormal Tyrosine Kinase Activity and Cancer: Malignant Transformation and Tumor AngiogenesisTyrosine kinase signaling is central to both the malignant transformation of cells and tumor angiogenesis.12 Malignant transformation often results from dysregulation of tyrosine kinase signaling. Constitutive activation (ie, ongoing, even in the absence of an activating signal) of tyrosine kinases has been implicated in ≈70% of cancers (Table 1).12 In leukemias and solid cancers, the gene encoding the causal (or contributory) kinase is either amplified or mutated; the former leads to overexpression of the kinase and the latter to a constitutively activated state. Both mechanisms drive proliferation of the cancerous clonal cells and/or prevent them from undergoing apoptosis. Table 1. Kinase Inhibitors in CancerAgentClassTarget(s)MalignanciesCardiovascular Toxicity/(Rate)/TypemAb indicates humanized monoclonal antibody; S/TKI, serine/threonine kinase inhibitor; ALL, acute lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; HES, hypereosinophilic syndrome; NSCLC, non–small-cell lung cancer; CLL, chronic lymphocytic leukemia; PCV, polycythemia vera; IMF, idiopathic myelofibrosis; mTOR, mammalian target of rapamycin; PKC, protein kinase C; HF, heart failure; CDK, cyclin-dependent kinase; and ACS, acute coronary syndrome. Please see text for additional abbreviations. For agents not yet FDA approved, efficacy in malignancies is projected.*NDA expected 2008.†NDA expected 2010.‡Effect on left ventricular ejection fraction has not been determined, and therefore these represent best guesses.Imatinib (Gleevec)TKIAbl1/2, PDGFRα/β, KitCML, Ph+ B-cell ALL, CMML, HES, GISTYes/(low)‡/HFDasatinib (Sprycel)TKIAbl1/2, PDGFRα/β, Kit, SRC familyCMLYes/(low to moderate)‡/HF, generalized edemaNilotinib (Tasigna)TKIAbl1/2, PDGFRα/β, KitCMLYes/(low)‡/QT prolongation, rare sudden deathSunitinib (Sutent)TKIVEGFR1/2/3, Kit, PDGFRα/β, RET, CSF-1R, FLT3RCC, GISTYes/(moderate)/HF, hypertensionLapatinib (Tykerb)TKIEGFR (ERBB1), ERBB2HER2+ breast cancerNoSorafenib (Nexavar)TKI S/TKIRaf-1/B-Raf, VEGFR2/3, PDGFRα/β, Kit, FLT3RCC, melanomaYes/(low)‡/ACS, hypertension, HFGefitinib (Iressa)TKIEGFR (ERBB1)NSCLCNo‡Erlotinib (Tarceva)TKIEGFR (ERBB1)NSCLC, pancreatic cancerNo‡Temsirolimus (Torisel)NovelmTOR (indirect; binds to FKBP12 and complex inhibits mTOR)RCCNo‡Trastuzumab (Herceptin)mAbERBB2HER2+ breast cancerYes/(moderate)/HFBevacizumab (Avastin)mAbVEGF-AColorectal cancer, NSCLCYes/(low to moderate)‡/arterial thrombosis, hypertensionCetuximab (Erbitux)mAbEGFR (ERBB1)Colorectal cancer, squamous cell carcinoma of head/neckNo‡Panitumumab (Vectibix)mAbEGFR (ERBB1)ColorectalNo‡Rituximab (Rituxan)mAbCD20B-cell lymphomaUnknownAlemtuzumab (Campath)mAbCD52B-cell CLLYes (in patients with mycosis fungoides/Sézary syndrome13)/HFLestaurtinib*TKIJAK2/FLT3PCV, IMFUnknownPazopanib*TKIVEGFRs; PDGFRs; KitRCCUnknownVandetanib*TKIVEGFR/EGFRNSCLCUnknownCediranib†TKIVEGFRNSCLCUnknownAlvocidib†S/TKICDKCLLUnknownEnzastaurin†S/TKIPKCβB-cell lymphomaUnknownCML is a classic example of a cancer that results from a genetic mutation that creates a constitutively active tyrosine kinase. Four decades ago, Peter Nowell first described the association of CML with the Philadelphia chromosome, which is created by a balanced translocation in myeloid precursors. The Philadelphia chromosome encodes a fusion protein of the Bcr (breakpoint cluster region) protein kinase and the NRTK Abl (named after Herbert Abelson, who first identified v-Abl, a viral oncogene in mice encoding the kinase).12 The Bcr-Abl fusion protein spontaneously forms homodimers consisting of 2 Bcr-Abl proteins that interact via the Bcr domains (Figure 1). This leads to constitutive activation of the Abl kinase portion of Bcr-Abl. Dimers of Bcr-Abl then activate multiple downstream signaling pathways that result primarily in inhibition of apoptosis in CML cells (Figure 1).12,14Download figureDownload PowerPointFigure 1. Mechanisms of carcinogenesis of Bcr-Abl in CML. Oligomerization and cross-phosphorylation (P) of Bcr-Abl fusion proteins (top) lead to constitutive activation of the Abl kinase domain. This leads (bottom) to activation of 3 key prosurvival pathways: STAT5, which leads to increased expression of antiapoptotic Bcl-XL; the Raf→ERK (or mitogen-activated protein kinase) pathway, which increases expression of antiapoptotic Bcl2; and the phosphoinositide-3 kinase→Akt pathway, a major antiapoptotic pathway in cancer cells and cardiomyocytes, that inhibits proapoptotic factors FOXO3a and Bad. This culminates in potent inhibition of apoptosis in CML cells.12In addition to driving tumorigenesis, tyrosine kinase signaling also plays a central role in mediating tumor angiogenesis. The vital role of tumor angiogenesis was proposed >3 decades ago by the pioneer Judah Folkman.15 Cancers more than a few millimeters in size are dependent on formation of new microvessels for their continued growth and ability to metastasize.15 Almost all of the proangiogenic growth factors that were subsequently identified (ie, VEGF, placental growth factor [PlGF], PDGF, transforming growth factor-α, and fibroblast growth factor) are ligands of RTKs.Inhibitors of Tyrosine Kinases as Anticancer AgentsThe dependency of certain cancers on 1 or just a few genes for maintenance of the malignant phenotype, termed oncogene addiction, provides a rationale for molecular targeting in cancer therapy.16 Inhibition of aberrant tyrosine kinase activity has become a central and exciting focus of anticancer therapy. Two classes of targeted tyrosine kinase therapeutics have been developed: humanized mAbs and small-molecule TKIs17 (Table 1; Figure 2). mAbs are antibodies produced from a single parent clonal cell. For anticancer therapy, mAbs are designed to bind the cancer cell–specific antigens, commonly to the extracellular portion of RTKs, thereby inhibiting tyrosine kinase activation (Figure 2). The binding of mAbs to the extracellular domain of the RTKs can block ligand binding to the receptor, inhibit subsequent dimerization and activation of the tyrosine kinase domain, and/or induce downregulation of expression of the receptor.17 Furthermore, mAbs also may induce an immune response against the targeted tumor cell. An example of a mAb that binds to receptors is trastuzumab (Herceptin; Genentech), which binds to the ERBB2 receptor (also known as HER2; Table 1). Other mAbs do not bind to the kinase receptors themselves but instead bind the growth factor ligands that activate the receptors. For example, bevacizumab (Avastin; Genentech) targets VEGF-A, thereby preventing it from interacting with the VEGF receptor and leading to inhibition of tumor angiogenesis. Download figureDownload PowerPointFigure 2. Mechanisms of action of mAbs vs small-molecule TKIs. Ligand (L) binding to RTKs leads to receptor dimerization, cross-phosphorylation (red lines and P), and activation of the intracellular tyrosine kinase domain (red boxes). Substrates are then phosphorylated, leading to cellular responses. mAbs (top) interfere with ligand binding to receptor and/or receptor dimerization and cross-phosphorylation, blocking activation of the RTKs.17 TKIs (bottom) do not prevent ligand binding or dimerization, but by preventing ATP from binding to the kinase domain, they block cross-phosphorylation of receptors and phosphorylation of substrates.The vast majority of small-molecule inhibitors used in cancer therapy are directed at tyrosine kinases, although some target serine/threonine kinases, the other superfamily of kinases involved in intracellular signaling (see below). Small-molecule inhibitors have been designed to target both classes of tyrosine kinases: RTKs and NRTKs. Inhibitors of RTKs block activity of the intracellular kinase domain. Normally, ligand binding to a RTK initiates dimerization and cross-phosphorylation of one kinase domain by the other, thereby activating the kinase (Figure 2). The activated kinase dimer then phosphorylates downstream substrates in a signaling cascade that ultimately results in changes such as altered gene expression and cell proliferation. TKIs can directly inhibit the cross-phosphorylation of the kinase domains and also inhibit phosphorylation of downstream substrates, thereby terminating the signaling cascade. TKIs that block signaling by NRTKs (eg, Abl) target intracellular kinases and work in a fashion similar to those that target RTKs.TKIs can block substrate phosphorylation in 3 ways (Okram et al18 and references therein). Substrate phosphorylation is dependent on the binding of both ATP and the substrate to an activated kinase. Type I inhibitors (eg, sunitinib) compete with ATP for binding to the ATP pocket of a fully activated kinase and are by far the dominant type in use today. However, they generally lack selectivity because of the highly conserved structure of the ATP pocket across the >500 kinases in the human genome and thus typically inhibit several kinases. Type II inhibitors (eg, imatinib and nilotinib) bind 2 different regions on the kinase: the ATP pocket and an adjacent region that is accessible only when the kinase is inactive. Type II inhibitors thus bind and lock kinases in an inactive state. Type II TKIs generally are more potent and more selective than type I. However, type II agents still typically inhibit ≥3 kinases (Table 1). Type III inhibitors (eg, the archetypal extracellular signal-regulated kinase [ERK] pathway inhibitors PD98059 and U0126) bind to sites remote from the ATP pocket, such as the substrate recognition region (blocking binding of substrate to kinase), or other regions of kinases that are much more divergent across the genome. Consequently, type III inhibitors promise to be the most selective. Despite their potential for greater selectivity, however, type III inhibitors represent a small minority of TKIs in development because they are more difficult to design and not as predictably effective. Overall, TKIs are inherently less selective than mAbs and typically inhibit several kinases, some known and others not.One particular subgroup of TKIs is the so-called multitargeted agents. Theoretically, agents that inhibit growth factors or their receptors involved in angiogenesis, as well as kinases involved in tumor cell proliferation, could have very broad anticancer activity arising from this dual pharmacological effect.19 This concept led to the development of the multitargeted agents sorafenib (Nexavar, Onyx-Bayer) and sunitinib (Sutent, Pfizer). This strategy, and its real and potential problems, will be discussed in detail below.Success With Targeted TherapeuticsMonoclonal antibodies and small-molecule TKIs have validated the “oncogene addiction theory” and greatly improved the management of certain cancers. Trastuzumab was the first FDA-approved targeted anticancer agent, and it was approved for the treatment of women with metastatic ERBB2-positive breast cancer. Overexpression of the ERBB2 receptor was associated with more poorly differentiated tumors, higher rates of metastases, and poorer patient survival.20 Trastuzumab, a recombinant, humanized, IgG mAb that binds to the extracellular domain of ERBB2, causes growth inhibition and apoptosis of tumor cells expressing ERBB2.12 In women with metastatic breast cancer, addition of trastuzumab to standard chemotherapy resulted in a 20% decrease in risk of death among patients at 1 year.5 Furthermore, in 5 phase III randomized trials of women with early stage ERBB2-positive breast cancer, trastuzumab used in the adjuvant setting after standard chemotherapy reduced the risk of disease recurrence at 3 years.20At about the same time, imatinib (Gleevec, Novartis), a drug that inhibits Bcr-Abl, the causal factor in 90% of the cases of CML, dramatically improved the survival of patients with this disease,4 leading to its approval by the FDA in 2001. Ninety percent of patients with CML treated with imatinib are alive 5 years after diagnosis of a disease that was uniformly fatal before this targeted therapy.4On the basis of the success of trastuzumab and imatinib, the development of targeted therapeutics has exploded in the last few years. Currently, there are 29 FDA-approved agents that inhibit kinase activity, 21 mAbs and 8 TKIs (Table 1).6,7 Three New Drug Application (NDA) filings for TKIs are expected in 2008 and an additional 3 in 2010 (Table 1). However, this number is truly the tip of the iceberg because there are ≈175 mAbs and 150 TKIs in clinical trials, with many more in preclinical development.6,7 Currently, there are ≈600 agents somewhere between discovery and market, with 80% being developed as anticancer agents. Although sales of TKIs were only ≈$4 billion in 2005–2006, with imatinib accounting for $2.5 billion, sales of TKIs are projected to grow substantially in the next few years.6Cardiac Side EffectsTargeted anticancer drugs were initially thought to affect tumors but not normal tissue in which kinases were not constitutively active. Thus, the hope of targeted therapy was high efficacy with minimal side effects. As with many drugs, clinical trials have revealed unanticipated side effects of targeted therapies involving the heart and other organs.21 Cardiovascular side effects have, in general, been able to be managed medically and typically have not prevented their use. Still, the need to use TKIs on a long-term basis emphasizes the importance of knowing which agents are associated with cardiac effects and understanding mechanisms that underlie that toxicity.Cardiovascular side effects of TKIs are varied and have included heart failure, LV dysfunction, conduction abnormalities, QT prolongation, acute coronary syndromes, myocardial injury, arterial thromboses, and hypertension8,9,14,22 (see Yeh23 for additional toxicities with cancer therapeutics in general). Overall, systolic dysfunction with resultant heart failure is one of the most common important side effects. This often occurs because pathways that induce the pathological survival and abnormal proliferation of cancer cells may also regulate the survival of normal cells, including cardiomyocytes. Targeting these pathways in cancer cells may inherently lead to on-target cardiotoxicity, manifest as cardiomyopathy, because of inhibition of these same prosurvival kinases in normal cardiomyocytes. We will introduce examples of on-target cardiotoxicity of the widely used drugs trastuzumab and imatinib and probable off-target toxicity of another popular agent, sunitinib, to illustrate molecular mechanisms of cardiotoxicity.TrastuzumabThe classic example of on-target cardiotoxicity of tyrosine kinase inhibition may be the cardiac effects of trastuzumab. As noted above, trastuzumab is directed at the ERBB2 RTK.5,24 Activation of ERBB2 leads to activation of intracellular signaling pathways in breast cancer cells similar to those seen with Bcr-Abl including ERK, PI3K/Akt, and signal transducer and activator of transcription 5 (STAT5), which drive tumor cell growth and prevent apoptosis (Figure 3).12,14 Trastuzumab is very effective in blocking activation of these signaling pathways in ERBB2+ breast cancer cells. Download figureDownload PowerPointFigure 3. Comparison of ERBB2 signaling and its inhibition by trastuzumab in breast cancer cells vs cardiomyocytes.14 In breast cancer cells overexpressing ERBB2, ERBB2 homodimers or ERBB2/ERBB3 heterodimers form, leading to constitutive activation of the ERK, PI3K/Akt, and STAT5 pathways (latter not shown). Akt blocks apoptosis by phosphorylating and inhibiting 2 key proapoptotic factors, Bad and FOXO3A, and also inactivates the cyclin-dependent kinase inhibitor p27, thereby enhancing cell proliferation. Trastuzumab blocks all downstream signaling, but particularly important may be reversing the inhibition of Bad, leading to activation of Bax, cyctochrome c (cyt c) release, and apoptosis. In cardiomyocytes exposed to Nrg1, ERBB2/ERBB4 heterodimers form, again activating ERK and Akt. Trastuzumab blocks this activation and, via multiple mechanisms including alterations in levels of Bcl-X family members,48 leads to mitochondrial dysfunction, energy compromise, and cytochrome c release. Trastuzumab also blocks Nrg1-mediated activation of Src and Fak, and this appears to worsen left ventricular dysfunction.49In a pivotal phase III clinical trial of trastuzumab efficacy, the addition of trastuzumab to anthracycline improved survival in women with metastatic breast cancer.5 However, cardiotoxicity was an unanticipated finding, with 27% of patients treated with the regimen of anthracycline, cyclophosphamide, and trastuzumab developing heart failure. Several large studies subsequently confirmed the importance of trastuzumab in increasing disease-free survival from cancer but also confirmed the association with heart failure (References 20 and 25 and references therein). When anthracyclines were not administered concurrently with trastuzumab, the incidence of LV dysfunction decreased to 13% in patients previously treated with anthracycline and then treated with paclitaxel and trastuzumab. In the adjuvant trials, 1.7% to 4.1% of trastuzumab-treated patients developed congestive heart failure.25 The incidence of cardiotoxicity of trastuzumab in nontrial settings is beginning to be examined. Recently, McArthur and Chia26 reported a 20% risk of left ventricular dysfunction in patients being treated with trastuzumab after anthracycline therapy when treated off trial.The finding of trastuzumab-induced heart failure in breast cancer patients led to a search for the molecular mechanisms of this effect. There was abundant evidence in mice that ERBB2 and its activating ligand, neuregulin-1 (Nrg1), play important roles during cardiac development. Germline deletion of ERBB227 or Nrg128 in mice is lethal in mid gestation with failure of the ventricles to form properly, suggesting that ERBB2 signaling is required for cardiomyocyte proliferation during development. Mice with cardiac-specific deletion of ERBB2, after cardiac development was complete, were viable. However, these mice developed dilated cardiomyopathy as they aged and had decreased survival when subjected to pressure overload induced by aortic banding (Table 2).29,30 Cardiomyocytes from these mice also exhibited enhanced sensitivity to anthracyclines, explaining in part the enhanced toxicity of the combination in patients.29Table 2. Evidence From Experimental Models Suggesting Cardiotoxicity of TKIs by Tyrosine Kinase TargetTyrosine Kinase Target(s)TKIsModelCardiac Phenotype of ModelReferencesN/A indicates not available; WT, wild-type; KO, knockout, gene deleted; HGF, hepatocyte growth factor (ligand for Met); FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; MI, myocardial infarction; LV, left ventricular; HF, heart failure; and TAC, thoracic aortic constriction. See text for other abbreviations.ERBB2Trastuzumab, lapatinibERBB2 KO: ±TACSpontaneous dilated cardiomyopathy; worsened heart failure with pressure load; enhanced anthracycline sensitivity29, 30VEGF, VEGFRsSunitinib, sorafenib, bevacizumabWT: VEGF trap+TACPathological remodeling in response to pressure load31–33KITImatinib/dasatinib, nilotinib, sunitinib, sorafenib(1) W/WV mouse (Kit-deficient)+MI; (2) WT: arterial injury+imatinib(1) Adverse remodeling after MI due to reduced homing of bone marrow stem cells to sites of injury; (2) reduced stenosis after arterial injury34–36Raf-1/B-RafSorafenibRaf-1 KO and dominant negative+TACLV dilatation and HF with pressure load37, 38PDGFRsImatinib/dasatinib, nilotinib, sunitinib, sorafenibWT: MI+administration of PDGFReduced injury (ischemic protection)39–41JAK2LestaurtinibSTAT3 KO: MI; aging; anthracycline administration; pregnancyIncreased ischemic injury; reduced capillary density with aging; increased anthracycline toxicity; peripartum cardiomyopathy42, 43Abl/ArgIimatinib/dasatinib, nilotinibWT: imatinibDecline in LV function; induction of ER stress9, 44Met (HGF receptor)N/AWT: MI or cardiomyopathy models+administration of HGFReduced fibrosis in MI and cardiomyopathy models; neoangiogenesis with HGF45 and references thereinFGFR1/3N/ACell culture models: administration of FGFEnhanced proliferation of cardiomyocytes and cardiac-resident stem cells46 and references thereinAs in cancer cells, Nrg1-induced activation of ERBB2 in cardiomyocytes activates the ERK and PI3K/Akt pathways that promote cardiomyocyte proliferation during development and cardiomyocyte survival during adulthood (Figure 3).47 The Src/focal adhesion kinase (Fak) pathway, which enhances cardiac contractility, is also activated by Nrg1.49 Expression of the antiapoptotic protein Bcl-XL in hearts of newborn mice by adenoviral gene transfer partially prevented the heart chamber dilation and the impaired contractility seen in the adult.29 Thus inhibition of ERBB2 signaling appears to lead to dysfunction and death both in breast cancer cells overexpressing the ERBB2 receptor and in normal cardiomyocytes (ie, on-target toxicity).Surprisingly, unlike trastuzumab, lapatinib (Tykerb, GlaxoSmithKline), the small-molecule dual inhibitor of ERBB2 and epidermal growth factor receptor (EGFR) (also known as ERBB1; Table 1), shows limited depression of cardiac function.50,51 Whereas future trials will be important to confirm this apparent absence of cardiac dysfunction, inherent differences in mechanism of action between mAbs and TKIs may also contribute to the different cardiotoxicity profiles reported between trastuzumab and lapatinib. mAbs, as opposed to small-molecule inhibitors, initiate antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity that could augment cardiotoxicity.17 Furthermore, differential inhibition/activation by lapatinib versus trastuzumab of downstream signaling pathways may also contribute to the difference in observed rates of heart failure and LV dysfunction. For example, lapatinib activates the cytoprotective AMP-activated protein kinase in cardiomyocytes, whereas trastuzumab does not.52 It is obviously critical to identify mechanisms of the apparent difference in cardiotoxicity with the 2 agents because it could significantly affect approaches to treatment of patients with ERBB2-positive breast cancer.ImatinibImatinib is indicated for the treatment of Philadelphia chromosome–positive CML and acute lymphocytic leukemia; GIST, driven by activating mutations in either c-Kit (the receptor for stem ce