Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice

Szymon Macioszek; Danuta Dudzik; Rafał Bartoszewski; Tomasz Stokowy; Diether Lambrechts; Bram Boeckx; Agnieszka Wozniak; Patrick Schöffski; Michał J Markuszewski

doi:10.1016/j.tranon.2023.101632

Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice

Transl Oncol. 2023 Apr:30:101632. doi: 10.1016/j.tranon.2023.101632. Epub 2023 Feb 10.

Authors

Szymon Macioszek¹, Danuta Dudzik¹, Rafał Bartoszewski², Tomasz Stokowy³, Diether Lambrechts⁴, Bram Boeckx⁴, Agnieszka Wozniak⁵, Patrick Schöffski⁵, Michał J Markuszewski⁶

Affiliations

¹ Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, Poland.
² Department of Biophysics, Faculty of Biotechnology, University of Wrocław, F. Joliot-Curie 14a Street, 50-383 Wrocław, Poland.
³ IT Division, University of Bergen, 5021, Bergen, Norway.
⁴ Laboratory of Translational Genetics, KU Leuven and VIB Center for Cancer Biology, Leuven, Belgium.
⁵ Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, and Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
⁶ Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, Poland. Electronic address: michal.markuszewski@gumed.edu.pl.

Abstract

Background: Although imatinib is a well-established first-line drug for treating a vast majority of gastrointestinal stromal tumours (GIST), GISTs acquire secondary resistance during therapy. Multi-omics approaches provide an integrated perspective to empower the development of personalised therapies through a better understanding of functional biology underlying the disease and molecular-driven selection of the best-targeted individualised therapy. In this study, we applied integrative metabolomic and transcriptomic analyses to elucidate tumour biochemical processes affected by imatinib treatment.

Materials and methods: A GIST xenograft mouse model was used in the study, including 10 mice treated with imatinib and 10 non-treated controls. Metabolites in tumour extracts were analysed using gas chromatography coupled with mass spectrometry (GC-MS). RNA sequencing was also performed on the samples subset (n=6).

Results: Metabolomic analysis revealed 21 differentiating metabolites, whereas next-generation RNA sequencing data analysis resulted in 531 differentially expressed genes. Imatinib significantly changed the profile of metabolites associated mainly with purine and pyrimidine metabolism, butanoate metabolism, as well as alanine, aspartate, and glutamate metabolism. The related changes in transcriptomic profiles included genes involved in kinase activity and immune responses, as well as supported its impact on the purine biosynthesis pathway.

Conclusions: Our multi-omics study confirmed previously known pathways involved in imatinib anticancer activity as well as correlated imatinib-relevant downregulation of expression of purine biosynthesis pathway genes with the reduction of respectful metabolites. Furthermore, considering the importance of the purine biosynthesis pathway for cancer proliferation, we identified a potentially novel mechanism for the anti-tumour activity of imatinib. Based on the results, we hypothesise metabolic modulations aiming at the reduction in purine and pyrimidine pool may ensure higher imatinib efficacy or re-sensitise imatinib-resistant tumours.

Keywords: GIST; Imatinib; Metabolomics; Multi-omics; Transcriptomics; purines.