Macioszek Szymon, Dudzik Danuta, Bartoszewski Rafał, Stokowy Tomasz, Lambrechts Diether, Boeckx Bram, Wozniak Agnieszka, Schöffski Patrick, Markuszewski Michał J
Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, Poland.
Department of Biophysics, Faculty of Biotechnology, University of Wrocław, F. Joliot-Curie 14a Street, 50-383 Wrocław, Poland.
Transl Oncol. 2023 Apr;30:101632. doi: 10.1016/j.tranon.2023.101632. Epub 2023 Feb 10.
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.
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).
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.
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.
尽管伊马替尼是治疗绝大多数胃肠道间质瘤（GIST）的成熟一线药物，但GIST在治疗过程中会产生继发性耐药。多组学方法通过更好地理解疾病背后的功能生物学以及分子驱动的最佳靶向个体化治疗选择，提供了一个综合视角来推动个性化治疗的发展。在本研究中，我们应用综合代谢组学和转录组学分析来阐明受伊马替尼治疗影响的肿瘤生化过程。
本研究使用了GIST异种移植小鼠模型，包括10只接受伊马替尼治疗的小鼠和10只未治疗的对照小鼠。使用气相色谱-质谱联用（GC-MS）分析肿瘤提取物中的代谢物。还对样本子集（n = 6）进行了RNA测序。
代谢组学分析揭示了21种差异代谢物，而新一代RNA测序数据分析产生了531个差异表达基因。伊马替尼显著改变了主要与嘌呤和嘧啶代谢、丁酸代谢以及丙氨酸、天冬氨酸和谷氨酸代谢相关的代谢物谱。转录组谱的相关变化包括参与激酶活性和免疫反应的基因，并支持其对嘌呤生物合成途径的影响。
我们的多组学研究证实了先前已知的参与伊马替尼抗癌活性的途径，以及与伊马替尼相关的嘌呤生物合成途径基因表达下调与相应代谢物减少之间的相关性。此外，考虑到嘌呤生物合成途径对癌症增殖的重要性，我们确定了伊马替尼抗肿瘤活性的一种潜在新机制。基于这些结果，我们假设旨在减少嘌呤和嘧啶库的代谢调节可能确保更高的伊马替尼疗效或使伊马替尼耐药肿瘤重新敏感。
