Table 1.

Selected tyrosine kinase inhibitors, their receptor targets, cardiotoxicity incidence and proposed cardiotoxic signaling mechanisms

Agents	Receptor Target(s)	Cardiotoxicity	Preclinical Models	Proposed Cardiotoxic Signaling Mechanisms	Reference
Axitiniba (Inlyta)	VEGFR-1, −2, −3 PDGFR-/β c-KIT	HTN AT QT Pericarditis LVSD	NA	NA	25,26,47
Cabozantiniba (Cabometyx)	VEGFR-2 CDK RET	HTN AT ↓ LVEF	NA	Inhibition of VEGFR-2 signaling leads to decreased expression of endothelial NO synthase and diminished NO synthesis, which disrupts the balance of NO and ET-1 promoting vasoconstriction, increased peripheral resistance, and increased blood pressure.a	26,47
Dasatinibb (Sprycel)	c-KIT PDGFR-/β EphA2 ABL BRAF Src kinase	CHF LVSD QT Thrombocytopenia HTN MI	Rat primary cardiomyocytes	Activation of ER stress response signaling leads to cellular apoptosis.	26,72,96
Gefitinib (Iressa)	EGFR1 (ERBB1)	MI	H9c2 ventricular cardiomyocytes	Increased expression of BNP and β-MHC along with decreased the levels of α-MHC, promotes cardiac hypertrophy in vivo and in vitro due to activation of cardiac apoptosis and oxidative stress pathways (ie, increased caspase-3, p53 and HO1).	97,99
Imatinib (Gleevec)	c-KIT Bcr-Abl PDGFR-/β	HTN QT IHD CHF LVSD	Rat primary cardiomyocytes	Activation of ER stress pathways, mitochondrial dysfunction, and increased ROS precipitates cellular apoptosis and necrosis in cultured cells and murine hearts. Increased expression of protein kinase Cδ (PKCδ), a kinase with pro-apoptotic effects in the heart.	26,34,95,96,100
Lapatinib (Tykerb)	EGFR1 (ERBB1) ERBB2	HTN QT ↓ LVEF LVSD	NA	Increased ratio of pro-apoptotic BCL-Xs to BCL-XL proteins, which may lead to ATP depletion, reduced cardiac contractility, and cardiac cell death via mitochondrial induced apoptosis.	26,99,100
Nilotinib (Tasigna)	Bcr-Abl DDR1/2 PDGFR-/β c-KIT	HTN QT IHD SCD	Rat primary cardiomyocytes	Activation of ER stress response pathways leading to cell death. Direct inhibition of hERG potassium channels reduce IKr promoting QT prolongation and arrhythmias.	26,72,96
Pazopaniba,b (Votrient)	VEGFR-1, −2, −3 PDGFR-/β c-KIT FGFR1/3 MCSFR-1 B-RAF	HTN AF HF Torsades de pointes AT LVSD	Atrial HL-1 cells; C57BL/6 Mice	Inhibition of VEGFR on cardiomyocytes reduces PI3K/Akt signaling leading to activation of proapoptotic pathways. Inhibition of FGFR-1 and −2 results in impaired cardiac response to stress and reduced contractility.	2,26,47
Ponatiniba (Iclusig)	Bcr-Abl FLT3 c-KIT VEGFR-2 PDGFR Src kinase FGFR1-3	HTN QT HF MI LVSD	hiPSC-induced cardiomyocytes; Zebrafish; NRVMs	Increased accumulation of ROS and mitochondrial dysfunction. Inhibition of cardiac Akt and Erk pro-survival signaling pathways leads to cardiomyocyte apoptosis.	26
Sunitiniba,b (Sutent)	VEGFR-1, −2, −3 PDGFR-/β RET c-KIT FLT3 CSF-1R	HTN HF QT ↓ LVEF LVSD	NRVMs; Swiss-webster Mice; Rat H9c2 cardiomyocytes; C57BL/6J mice	Inhibition of AMPK-mTOR signaling, ATP depletion, and impaired energy homeostasis promotes cardiomyocyte autophagy and death and contributes to LVSD. Inhibition of the RSK protein promotes mitochondrial dysfunction, which increases the release of cytochrome C (cyto C), and activation of caspase 9. Increased cyto C and activated caspase 9 initiates the mitochondrial apoptotic pathway in vitro and in vivo. Induction of cardiomyocyte apoptosis in presence of underlying cardiac pathology (HTN).	26,55,100,89,95,100
Sorafeniba,b. (Nexavar)	VEGFR-1, −2, −3 PDGFR-β B-RAF/C-RAF c-KIT FLT3	HTN HF MI QTc CHF LVEF AT	Zebrafish; NRVMs	Inhibition of Ras/Raf-1/Mek/Erk signaling pathway promotes mitochondrial dysfunction and apoptosis, which reduces cardiac cell survival. Increased activated CaMKII (ie, phosphorylated, and oxidized CaMKII), and ROS expression leads to pre-ventricular contractions and dysregulation in Ca+ homeostasis.	10,24,26,47,89,100
Vandetaniba. (Caprelsa)	VEGFR-1, −2, −3 EGFR PDGFR-β RET	HTN HF AF QT Torsades de pointes SCD	Postmortem human cardiac tissue;	Induced myocyte degeneration in the subendocardial zones and papillary muscles of the myocardium.	26,34,47,59
Vemurafenibb (Zelboraf)	B-RAF	HTN QT CHF	HEK293 T; Isolated canine Purkinje fibers	Inhibition of Braf increases cAMP activity with subsequent increases in PKA. PKA phosphorylation of hERG channels and reduces their ability to open during, which prolongs the repolarization period and contributes to prolonged QT intervalb and development of arrhythmias.	2,34,71

Abbreviations: AF, atrial fibrillation; AMPK, AMP-activated protein kinase; AT, arterial thromboembolism; ATP, adenosine triphosphate; Bcr-Abl, breakpoint cluster region-Abelson; BNP, brain naturietic peptide; CaMKII, calcium/calmodulin-dependent protein kinase; cAMP, cyclic adenosine monophosphate; CDK, cyclin-dependent kinase; CHF, congestive heart failure; c-KIT, stem cell factor receptor; CSF-1R, colony-stimulating factor 1 receptor; DDR1/2, Discoidin domain receptor 1; 2, EGFR; epidermal growth factor receptor, EGFR; epidermal growth factor receptor, EPHA2; ephrin type-A receptor 2, ER; endoplasmic reticulum, ERK; extra-cellular-signal-regulated kinase, ET-1; endothelin-1, FGFR1/2; fibroblast growth factor receptor, FLT3; FMS-related tyrosine kinase 3, HEK293 T; human embryonic kidney cells 293 T, hERG; human ether-a-go-go-related gene, HF; heart failure, hiPSC; human induced pluripotent stem cells, HL1-HTN; hypertension, HO1; heme oxygenase 1, IHD; ischemic heart disease, I_Kr; potassium currents, LVEF; left ventricular ejection fraction, LVSD; left ventricular systolic dysfunction, MCSFR-1; macrophage colony-stimulating factor-1 receptor, MHC; myosin heavy chain, MI; myocardial ischemia/infarction, NO; nitric oxide, NRVMs; Neonatal rat ventricular myocytes, PDGFR; platelet derived growth factor receptors, PI3K; phosphoinositide 3-kinase, PKA; protein kinase A, QT; QT prolongation, RET; rearranged during transfection, ROS; reactive oxygen species, RSK; ribosomal S6 kinase, SCD; sudden cardiac death, Src; short for sarcoma-proto-oncogene, TKI; tyrosine kinase inhibitors, VEGFR; vascular endothelial growth factor receptors.

^aNote (s): All VEGFR-TKIs have the potential to cause hypertension via this molecular mechanism. Further, the mechanisms leading to VEGFR-TKIs is multifactorial and might be related to microvascular dysfunction, ATP depletion in the mitochondria, myocardial proapoptotic kinases, microvascular dysfunction, and profound vasoconstriction.

^bAll B-RAF inhibitors have the potential to promote QTc prolongation by this mechanism.⁶⁸ (NA) indicates that to the authors knowledge there are no preclinical studies, which directly evaluated these drugs on cardiomyocyte tissue.