Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Force, Thomas; Krause, Daniela; Etten, Richard A. Van

doi:10.1038/nrc2106

Cited by 719 publications

(643 citation statements)

References 110 publications

(114 reference statements)

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“…For example, grade 3 to 4 left ventricular dysfunction has been observed to occur with greater frequency with sunitinib treatment than with either bevacizumab or sorafenib (0.3%, 1.4%, and 0.05% in phase I-III studies), suggesting a potential off-target effect (72). One potential explanation may be that the reduced left ventricular ejection fraction is a result of sunitinib-induced hypothyroidism (24). Another example is that dermatologic toxicities, specifically handfoot skin reactions, occur much less commonly in patients treated with bevacizumab than in those treated with sunitinib.…”

Section: Resultsmentioning

confidence: 99%

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Aparicio-Gallego

Blanco

Figueroa

et al. 2011

Molecular Cancer Therapeutics

102

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The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events. Mol Cancer Ther; 10(12); 2215-23. Ó2011 AACR.

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Section: Resultsmentioning

confidence: 99%

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Aparicio-Gallego

Blanco

Figueroa

et al. 2011

Molecular Cancer Therapeutics

102

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“…HBEGF null mice have been shown to develop severe dilated cardiomyopathy with enlarged ventricular chambers and diminished contractile function due to impaired phosphorylation of ERBB2/B4 tyrosine kinase receptors (Iwamoto et al 2003). It is also of note that in humans, cardiac side effects are reported in breast cancer patients upon treatment with Herceptin (Force et al 2007), a monoclonal antibody for the ERBB2 receptor tyrosine kinase, which acts through disruption of EGF ligand signaling (Iwamoto et al 2003). IK encodes a cytokine known to downregulate expression of HLA class II antigens (Krief et al 1994).…”

Section: Three Cosegregating Genes Determine Dcmmentioning

confidence: 96%

HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy

Friedrichs¹,

Zugck²,

Rauch³

et al. 2008

Genome Res.

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Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary.

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“…PERK phosphorylates the eukaryotic translation initiation factor 2a (EIF2a) as part of a protective response, and on sustained ER stress, IRE1 activates Jun N-terminal kinases (JNKs), leading to the phosphorylation of 14-3-3 and release of BAX followed by mitochondrial depolarization, ATP depletion, cytochrome c (Cyt c) release, and features of necrotic and apoptotic cell death. Adapted from Force et al 107 percentage of their CML patients enrolled in the IRIS trial (described in detail above). 47 In a subsequent case-control study, 16 of 24 (67%) CML patients developed hypophosphatemia on imatinib.…”

Section: Src Kinase Inhibition: Myelosuppressionmentioning

confidence: 99%

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

2009

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Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML), offering patients several targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the availability of imatinib, nilotinib and dasatinib, physicians must weigh the efficacy and safety profile of each agent when choosing the best therapeutic option for individual patients. Each agent targets tyrosine kinases within the cell uniquely to cause the desired antiproliferative effect. In addition to inhibiting the BCR-ABL kinase, imatinib and nilotinib target the same array of other tyrosine kinases, including c-KIT and plateletderived growth factor receptor (PDGFR), albeit with differing potencies. While targeting BCR-ABL with the highest potency among approved agents in CML, dasatinib also targets a broad array of off-target kinases, including SRC family members, PDGFR and EPHB4. The differences in kinase inhibition profiles among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the various kinases inhibited by imatinib, nilotinib and dasatinib, and describes the potential impact of kinase inhibition on the efficacy and safety of each agent.

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Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Cited by 719 publications

References 110 publications

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

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