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24.08.2022 | Original Article

SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib

verfasst von: Yan Chen, Rui Zhang, Dandan Mi, Qiuju Wang, Tingwenli Huang, Xinwei Dong, Hongwei Zhang, Hongtao Xiao, Sanjun Shi

Erschienen in: Gastric Cancer | Ausgabe 1/2023

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Abstract

Background

Imatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1–3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites.

Methods

This study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism.

Results

The results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance.

Conclusions

Our findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs.

Graphical abstract

The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells.

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Titel: SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib
verfasst von: Yan Chen
Rui Zhang
Dandan Mi
Qiuju Wang
Tingwenli Huang
Xinwei Dong
Hongwei Zhang
Hongtao Xiao
Sanjun Shi
Publikationsdatum: 24.08.2022
Verlag: Springer Nature Singapore
Erschienen in: Gastric Cancer / Ausgabe 1/2023
Print ISSN: 1436-3291
Elektronische ISSN: 1436-3305
DOI: https://doi.org/10.1007/s10120-022-01332-7

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SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib