Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

Takahiro Amemiya, Masashi Honma, Yoshiaki Kariya, Samik Ghosh, Hiroaki Kitano, Yoshihisa Kurachi, Ken-ichi Fujita, Yasutsuna Sasaki, Yukio Homma, Darrel R Abernethy, Haruki Kume, Hiroshi Suzuki

ABSTRACT

BACKGROUND/OBJECTIVES: Targeted kinase inhibitors are an important class of agents in anticancer therapeutics, but their limited tolerability hampers their clinical performance. Identification of the molecular mechanisms underlying the development of adverse reactions will be helpful in establishing a rational method for the management of clinically adverse reactions. Here, we selected sunitinib as a model and demonstrated that the molecular mechanisms underlying the adverse reactions associated with kinase inhibitors can efficiently be identified using a systems toxicological approach. METHODS: First, toxicological target candidates were short-listed by comparing the human kinase occupancy profiles of sunitinib and sorafenib, and the molecular mechanisms underlying adverse reactions were predicted by sequential simulations using publicly available mathematical models. Next, to evaluate the probability of these predictions, a clinical observation study was conducted in six patients treated with sunitinib. Finally, mouse experiments were performed for detailed confirmation of the hypothesized molecular mechanisms and to evaluate the efficacy of a proposed countermeasure against adverse reactions to sunitinib. RESULTS: In silico simulations indicated the possibility that sunitinib-mediated off-target inhibition of phosphorylase kinase leads to the generation of oxidative stress in various tissues. Clinical observations of patients and mouse experiments confirmed the validity of this prediction. The simulation further suggested that concomitant use of an antioxidant may prevent sunitinib-mediated adverse reactions, which was confirmed in mouse experiments. CONCLUSIONS: A systems toxicological approach successfully predicted the molecular mechanisms underlying clinically adverse reactions associated with sunitinib and was used to plan a rational method for the management of these adverse reactions. More... »

PAGES

15005

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/npjsba.2015.5

DOI

http://dx.doi.org/10.1038/npjsba.2015.5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008725408

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28725458


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