Table 2.

Evidence from experimental models suggesting cardiotoxicity of TKIs by TK target.

TK target(s)	TKIs	Model	Cardiac phenotype of model	References
ERBB2	trastuzumab lapatinib	ERBB2 KO: ±TAC	Spontaneous dilated CMP; worsened heart failure with pressure load; enhanced anthracycline sensitivity.	29, 30
VEGF VEGFRs	sunitinib sorafenib bevacizumab	WT: VEGF Trap + TAC	Pathologic remodeling in response to pressure load.	31–33
KIT	imatinib/D/N sunitinib sorafenib	1) W/WV mouse (KIT-deficient) + MI 2) WT: Arterial injury + imatinib	1) Adverse remodeling post MI due to reduced homing of bone marrow stem cells to sites of injury; 2) Reduced stenosis post arterial injury.	34–36
Raf-1/B- Raf	sorafenib	Raf-1 KO and dominant negative + TAC	LV dilatation and CHF with pressure load.	37, 38
PDGFRs	imatinib/D/N sunitinib sorafenib	WT: MI + Administration of PDGF	Reduced injury (ischemic protection).	39–41
JAK2	lestaurtinib	STAT3 KO: MI; aging; anthracycline administration; pregnancy	Increased ischemic injury; reduced capillary density with aging; increased anthracylcine toxicity; peri-partum cardiomyopathy.	42, 43
Abl/Arg	imatinib/D/N	WT: imatinib	Decline in LV function; induction of ER stress.	9, 44
Met (HGF receptor)	N/A	WT: MI or CMP models + administration of HGF	Reduced fibrosis in MI and CMP models. Neoangiogenesis with HGF.	45 and refs. therein
FGFR1/3	N/A	Cell culture models: Administration of FGF	Enhanced proliferation of cardiomyocytes and cardiac-resident stem cells.	46 and refs. therein

Abbreviations: WT, wild type; KO, knockout- gene deleted; D/N, dasatinib, nilotinib; ER, endoplasmic reticulum; CMP, cardiomyopathy

HGF, hepatocyte growth factor (ligand for Met); FGFR fibroblast growth factor receptor; MI, myocardial infarction.

See text for other abbreviations.