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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number15005
Journalnpj Systems Biology and Applications
Volume1
DOIs
Publication statusPublished - Sep 28 2015

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ASJC Scopus subject areas

  • Computer Science Applications
  • Applied Mathematics
  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)
  • Drug Discovery

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