Systems pharmacology of tyrosine kinase inhibitor-associated toxicities

Abstract

Tyrosine kinase inhibitors (TKIs) are designed to exhibit marked efficacy against cancer progression, based on accumulated molecular knowledge. The administration of TKIs is associatedwithmuch lower general toxicities (such as pancytopenia and gastrointestinal tract disturbance) than the administration of classical cytotoxic anti-tumor agents. However, TKIs provoke certain adverse reactions, which cannot be explained by the molecular mechanisms known at the time of drug development. Unfortunately, these unfavorable events often force the discontinuation of TKI treatment, with a typical worsening of therapeutic outcomes. Therefore, elucidating the molecular mechanisms behind TKI-related adverse reactions is a critical task in current and future chemotherapeutic drug management. Here, we provide a concrete mechanistic investigation of the adverse reactions of erlotinib, a TKI prototype, using a systems pharmacology-based approach. The molecular mechanism of erlotinib remains largely unknown, probably because there has been no unbiased drug analysis or account taken of the information available in numerous archives. In this study, we separated the mechanismof skin inflammation, a prominent erlotinib-mediated adverse reaction, into multiple pharmacokinetic/pharmacodynamic layers constituting drug responses. Importantly, an examination of the candidate mechanisms associated wiTheach layer effectively extracted mechanisms from a myriad of contenders, enabling the design of polished “wet” experiments for further confirmation. This strategy is conceptually applicable to drugs other than erlotinib, and might facilitate the mechanistic exploration of the adverse reactions of cancer drugs in general.