Sensitive Metabolites and Single Nuclear Polymorphisms of OCT1 on Imatinib Meyslate in Patients with Gastrointestinal Stromal Tumors (GISTs)

Abstract

Imatinib mesylate (IM) is highly efficacious in the treatment of gastrointestinal stromal tumors (GISTs). Therapeutic drug monitoring (TDM) and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to explore the most sensitive metabolites and the role of organic cation transporter 1 (OCT1) on single nuclear polymorphisms (SNP) of IM treatment, which could supply a greater mechanistic understanding of therapeutic effect or resistance of IM. A total of 40 human serum samples from patients with GISTs were collected for TDM. Basing on the results of TDM, the untargeted metabolomic analysis was to determine characteristics of the serum. Principal component analysis (PCA), orthogonal partial least-squares discrimination analysis (OPLS-DA), and heat map were used for multivariate analysis. In addition, KEGG database were used to identify the pathways of metabolites. Differential metabolites were identified based on a heat map with a t-test threshold (p < 0.05), fold-change (FC) threshold (FC > 1.5 or FC < 2/3) and variable importance (VIP) in the projection (VIP>1). The potential differential metabolites were included D-sphingosine, 1-sphingosine phosphate, phytosphingosine and phosphoethanolamine, which were belonged to the metabolism pathway of sphingolipid. Because of the function of OCT1 transporters was related with drug in the liver, the OCT1 1386C>A (rs 622342) was statistically significant (P<0.05) with IM plasma concentration. Thus, this study demonstrated that sphingolipid metabolism should be considered as the potential pathway of IM treated GISTs, which could bring us a clue to new mechanism for IM treatment of patients with GISTs.