Table 3.

New Cancer Therapies and Proposed Mechanisms of Cardiovascular Toxicity

Oncological target(s)	Agents	Reported toxicity	Preclinical models	Proposed pathways
KIs
HER2 (ErbB2)	Trastuzumab Trastuzumab-emtansine Pertuzumab Lapatinib Neratinib	Cardiomyopathy	hiPSC-CMs⁴ Primary cardiomyocytes Mice (genetic deletion of ERBB2)³²	Alterations in cellular and metabolic pathways (eg, AMP kinase⁴)
VEGF, PDGF	Sunitinib Sorafenib Pazopanib Vandetanib Axitinib Regorafenib Cabozantinib Bevacizumab	Cardiomyopathy Vascular disease Hypertension Thrombotic microangiopathy QT prolongation	hiPSC-CMs Primary cardiomyocytes Mice	Inhibition of VEGF/PDGF Capillary rarefaction Induction of HIFs in the myocardium³³ Suppression of PI3K signaling³⁴ Decreased NO production
BCR-ABL^*	Nilotinib Dasatinib Imatinib Ponatinib Bosutinib	Hyperglycemia (nilotinib) Pulmonary hypertension, pericardial and pleural effusion (dasatinib) Vascular events (nilotinib, ponatinib)		VWF-mediated platelet adhesion leading to thrombotic microangiopathy (ponatinib)³⁵ Suppression of PI3K signaling³⁴ Decreased NO production
EGFR	Dacomitinib Erlotinib Gefitinib Osimertinib Cetuximab Panitumumab	Osimertinib: QT prolongation Atrial fibrillation Heart failure Cardiomyopathy Pericardial effusion None with other agents	hiPSC-CMs	Not defined
BTK	Ibrutinib Acalabrutinib	Arrhythmia (supraventricular, particularly atrial fibrillation/flutter; ventricular)	Mice	Abnormal Ca²⁺ handling in atrial myocytes and reduced sarcoplasmic Ca²⁺ capacity Atrial fibrosis
Raf/MEK	Trametinib Cobimetinib Selumetinib	Cardiomyopathy	Mice (Erk1^−/− and Erk2^+/−)	Not defined
CDK4/6	Ribociclib	QT prolongation	Rodent	Not defined
PI3K/mTOR	Temsirolimus Everolimus	Metabolic Hyperlipidemia Hyperglycemia Peripheral edema	Rodent	Decreased insulin secretion
MCL-1	Investigational	Cardiomyopathy	Rodent (Mcl-1 conditional KO mice)	Not defined
ALK	Crizotinib Ceritinib Alectinib Brigatinib Lorlatinib	Bradycardia	Rodent	Not defined
Drugs affecting protein degradation
Proteasome	Bortezomib Carfilzomib Ixazomib	Vascular events Hypertension Carfilzomib: Cardiomyopathy	Rodent Primary cardiomyocytes	Myocardial protein turnover
E3 ubiquitin ligase	IMiDs: Thalidomide Lenalidomide Pomalidomide	Venous and arterial thrombotic events	Rodents Human embryonic stem cells	Upregulation of prothrombotic factors (VWF, platelet activation)
Immune therapies
Immune checkpoints Cancer-specific antigens T-cell engagers High-dose cytokines (eg, IL-2) CD52 CD20	ICIs: Anti–CTLA-4: Ipilimumab Tremelimumab Anti–PD-1 Nivolumab Pembrolizumab Cemiplimab Anti–PDL1: Atezolizumab Avelumab Durvalumab CAR T-cell therapy: Axicabtagene ciloleucel Tisagenlecleucel Brexucabtagene autoleucel Bispecific T-cell engager antibodies: Blinatumomab	Myocarditis Cardiomyopathy Pericarditis Pleural effusion Vasculitis Vascular leak Thrombosis Tachyarrhythmia Bradyarrhythmia/heart block Cytokine release syndrome Atherosclerosis	Mice (CTLA4^−/−, PD-1^−/−)	IgG autoantibodies³⁶ T-cell activation T-cell and macrophage infiltration into myocardium³⁷

ALK indicates anaplastic lymphoma kinase; BCR-ABL, breakpoint cluster region-abelson protooncogene; BTK, Bruton tyrosine kinase; CAR, chimeric antigen receptor; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; ErbB2, erythroblastic oncogene B; HER2, human epidermal growth factor receptor 2; HIF, hypoxia-inducible factor; hiPSC-CM, human induced pluripotent stem cell—derived cardiomyocyte; ICI, immune checkpoint inhibitor; IgG, immunoglobulin G; IL-2, interleukin-2; IMiD, immunomodulatory imide drug; KI, kinase inhibitor; KO, knockout; MCL-1, myeloid-cell leukemia 1; MEK, mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; NO, nitric oxide; PD-1, programmed cell death protein-1; PDGF, platelet-derived growth factor; PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma; VEGF, vascular endothelial growth factor; and VWF, von Willebrand factor.

Agents that target BCR-ABL may also inhibit the VEGF pathway (eg, ponatinib).