10779/rcsi.10790546.v1
Alice C. O'Farrell
Alice C.
O'Farrell
Ian S. Miller
Ian S.
Miller
Rhys Evans
Rhys
Evans
Marina Alamanou
Marina
Alamanou
Maurice Cary
Maurice
Cary
Girish Mallya Udupi
Girish Mallya
Udupi
Adam Lafferty
Adam
Lafferty
Naser Monsefi
Naser
Monsefi
Mattia Cremona
Mattia
Cremona
Jochen HM Prehn
Jochen HM
Prehn
Henk M. Verheul
Henk M.
Verheul
William M. Gallagher
William M.
Gallagher
Mathias Gehrmann
Mathias
Gehrmann
Annette Byrne
Annette
Byrne
Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre-Clinical Detection of Off-Target Toxicities Associated with Sunitinib Malate.
Royal College of Surgeons in Ireland
2019
Off-target toxicity
preclinical models
reverse phase protein arrays
sunitinib
tyrosine kinase inhibitors.
Physiology
Medical Physics
2019-11-23 11:40:25
Journal contribution
https://repository.rcsi.com/articles/journal_contribution/Implementing_Reverse_Phase_Protein_Array_Profiling_as_a_Sensitive_Method_for_the_Early_Pre-Clinical_Detection_of_Off-Target_Toxicities_Associated_with_Sunitinib_Malate_/10790546
<p><strong>PURPOSE:</strong> 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.</p>
<p><strong>EXPERIMENTAL DESIGN:</strong> 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</p>
<p><strong>RESULTS:</strong> 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.</p>
<p><strong>CONCLUSIONS AND CLINICAL RELEVANCE:</strong> 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.</p>