Quantitative Mass Spectrometry Imaging Reveals Mutation Status-independent Lack of Imatinib in Liver Metastases of Gastrointestinal Stromal Tumors
Quantitative Mass Spectrometry Imaging Reveals Mutation Status-independent Lack of Imatinib in Liver Metastases of Gastrointestinal Stromal Tumors
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DOI：
10.1038/s41598-019-47089-5
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发表时间：
2019-07-23
影响因子：
4.6
通讯作者：
Hopf, Carsten
中科院分区：
文献类型：
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作者：
Abu Sammour, Denis;Marsching, Christian;Hopf, Carsten
质谱学成像(MSI)是一种能够在生命科学和制药研究中以高空间分辨率进行无标记药物处置研究的技术。我们首次提出了广泛的临床基质辅助激光解吸/电离(MALDI)定量质谱学成像(QMSI)研究药物在临床标本中的摄取和分布，分析了27例经活检证实的罕见疾病胃肠道间质瘤(GIST)患者的56例肿瘤和相应的非肿瘤组织。为了验证，我们比较了MALDI-TOF-qMSI和传统的基于UPLC-ESI-QTOF-MS的组织提取物定量和超高分辨率MALDI-FTICR-qMSI。我们引入了一个新的基于含药区域计算评估的广义非线性药物数量校准模型，使得能够更好地进行数据拟合和评估固有方法的非线性。伊马替尼的组织空间图谱显示，药物对GIST肝转移瘤的药物渗透效率显著低下，尽管附近相应的健康肝组织显示出丰富的伊马替尼水平，超过了定量限制(LOQ)，从而提供了与突变状态无关的继发性耐药的证据。综上所述，这些发现强调了MALDI-qMSI在研究分子靶向治疗在肿瘤学中的空间分布方面的重要应用，即作为手术后评估抗癌药物处置对耐药的贡献的正交方法。
Mass spectrometry imaging (MSI) is an enabling technology for label-free drug disposition studies at high spatial resolution in life science- and pharmaceutical research. We present the first extensive clinical matrix-assisted laser desorption/ionization (MALDI) quantitative mass spectrometry imaging (qMSI) study of drug uptake and distribution in clinical specimen, analyzing 56 specimens of tumor and corresponding non-tumor tissues from 27 imatinib-treated patients with the biopsy-proven rare disease gastrointestinal stromal tumors (GIST). For validation, we compared MALDI-TOF-qMSI with conventional UPLC-ESI-QTOF-MS-based quantification from tissue extracts and with ultra-high resolution MALDI-FTICR-qMSI.We introduced a novel generalized nonlinear calibration model of drug quantities based on computational evaluation of drug-containing areas that enabled better data fitting and assessment of the inherent method nonlinearities. Imatinib tissue spatial maps revealed striking inefficiency in drug penetration into GIST liver metastases even though the corresponding healthy liver tissues in the vicinity showed abundant imatinib levels beyond the limit of quantification (LOQ), thus providing evidence for secondary drug resistance independent of mutation status. Taken together, these findings underscore the important application of MALDI-qMSI in studying the spatial distribution of molecularly targeted therapeutics in oncology, namely to serve as orthogonal post-surgical approach to evaluate the contribution of anticancer drug disposition to resistance against treatment.