Off-target toxicity, preclinical models, reverse phase protein arrays, sunitinib, tyrosine kinase inhibitors.
AngioTox [www.angiotox.com], a European Commission FP7 Industry Academia Pathways and Partnerships Marie Curie Award (Grant Agreement 251528). AngioPredict, an EU funded Seventh Framework Programme (Contract No. 278981). European Union’s Horizon 2020 research and innovation programme “Colossus” under grant agreement No. 754923.
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
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.
Physics | Physiology
O'Farrell AC, Miller IS, Evans R, Alamanou M, Cary M, Mallya Udupi G, Lafferty A, Monsefi N, Cremona M, Prehn JHM, Verheul HM, Gallagher WM, Gehrmann M, Byrne AT. Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre-Clinical Detection of Off-Target Toxicities Associated with Sunitinib Malate. Proteomics. Clinical applications. 2019:e1800159.
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