Journal
PROTEOMICS CLINICAL APPLICATIONS
Volume 13, Issue 4, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/prca.201800159
Keywords
off-target toxicity; preclinical models; reverse phase protein arrays; sunitinib; tyrosine kinase inhibitors
Funding
- AngioTox, a European Commission FP7 Industry Academia Pathways and Partnerships Marie Curie Award [251528]
- EU [278981]
- European Union [754923]
- H2020 Societal Challenges Programme [754923] Funding Source: H2020 Societal Challenges Programme
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Purpose The tyrosine kinase inhibitor (TKI) sunitinib is a multi-targeted agent approved across multiple cancer indications. Nevertheless, since approval, data has emerged to describe a worrisome side effect profile including hypertension, hand-foot syndrome, fatigue, diarrhea, mucositis, proteinuria, and (rarely) congestive heart failure. It has been hypothesized that the observed multi-parameter toxicity profile is related to on-target kinase inhibition in off-target tissues. Experimental Design To interrogate off-target effects in pre-clinical studies, a reverse phase protein array (RPPA) approach is employed. Mice are treated with sunitinib (40 mg kg(-1)) for 4 weeks, following which critical organs are removed. The Zeptosens RPPA platform is employed for protein expression analysis. Results Differentially expressed proteins associated with damage and/or stress are found in the majority of organs from treated animals. Proteins differentially expressed in the heart are associated with myocardial hypertrophy, ischaemia/reperfusion, and hypoxia. However, hypertrophy is not evidenced on histology. Mild proteinuria is observed; however, no changes in renal glomerular structure are visible via electron microscopy. In skin, proteins associated with cutaneous inflammation, keratinocyte hyper-proliferation, and increased inflammatory response are differentially expressed. Conclusions and Clinical Relevance It is posited that pre-clinical implementation of a combined histopathological/RPPA approach provides a sensitive method to mechanistically elucidate the early manifestation of TKI on-target/organ off-target toxicities.
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