Table I.

Representative tyrosine kinase inhibitors that cause cardiotoxicity.

Target no.	Agent (trade name)	Class	Targets	Malignancies	Cardiotoxicity incidence	First FDA approval	Molecular mechanism
Single	Trastuzumab (Herceptin)	mAb	ErbB2 (HER2)	HER2+ breast cancer	LVD: 3–7% as a single agent and ≤64% in combination regimens (>6 months administration)	1998	LVD: inactivation of HER2/Erk/Akt pathway in cardiomyocytes; prevention of HER2 receptor dimerization; tumor cell death; downregulation of HER2 receptor
	Bevacizumab (Avastin)	mAb	VEGF	mCRC, nsNSCLC, mRCC, GBM	LVD: 1.7–3%; HTN: 16–47%	2004a	HTN: inhibition of VEGF-eNOS to weaken vasodilation; overproliferation of vascular SMCs Thrombosis: increased platelet aggregation and proinflammatory gene expression in endothelial cells
Multiple	Imatinib (Gleevec)	Small molecule	ABL1/2, KIT, PDGFR α/β	CML, RCC, GIST, HES	HF: 0.5–1.7%	2001	HF: inhibition of ABL causes cardiomyopathy, increased apoptosis and ER stress
	Sunitinib (Sutent)	Small molecule	VEGFRs, PDGFR α/β, KIT, FLT3	RCC, imatinib resistant GIST	HF: 2.7–11%; HTN: 5–47%	2006	HF: abnormal mitochondrial biogenesis, increased apoptotic cell death, inhibition of AMPK and PDGFRs

^aApproved for breast cancer and revoked in 2011. FDA, Food and Drug Administration; mAb, monoclonal antibody; HER2, human epidermal growth factor receptor 2; LVD, left ventricular dysfunction; mCRC, metastatic colorectal cancer; nsNSCLC, non-squamous non-small-cell lung cancer; mRCC, metastatic renal cell carcinoma; GBM, glioblastoma multiforme; VEGF, vascular endothelial growth factor; eNOS, endothelial nitric oxide synthase; HTN, hypertension; SMC, smooth muscle cell; PDGFR, platelet-derived growth factor receptor; VEGFR, VEGF receptor; CML, chronic myelogenous leukemia; GIST, gastrointestinal stromal tumor; HES, hypereosinophilic syndrome; HF, heart failure; ER, endoplasmic reticulum; FLT-3, Fms-like tyrosine kinase 3; AMPK, AMP-activated protein kinase.