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Proteomics Clin Appl. 2019 Jul;13(4):e1800159. doi: 10.1002/prca.201800159. Epub 2019 Mar 19.

Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre-Clinical Detection of Off-Target Toxicities Associated with Sunitinib Malate.

Author information

1
RCSI Centre for Systems Medicine, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, D02 HX03, Ireland.
2
OncoMark Ltd., NovaUCD, Bellfield, University College Dublin, Dublin 4, D04 V2P1, Ireland.
3
Pathology Experts GmBH, Basel, CH-4108, Switzerland.
4
Beaumont Education Resource Centre, Beaumont Hospital, Dublin 9, D09 YD60, Ireland.
5
Department of Medical Oncology, VU University Medical Centre, Amsterdam, 1081HV, The Netherlands.
6
UCD Cancer Biology and Therapeutics Laboratory, School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, D04 W6F6, Ireland.
7
Bayer AG, Wuppertal, 42117, Germany.

Abstract

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.

KEYWORDS:

off-target toxicity; preclinical models; reverse phase protein arrays; sunitinib; tyrosine kinase inhibitors

PMID:
30768761
DOI:
10.1002/prca.201800159

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