Abstract
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.
Highlights
Www.nature.com/scientificreports much effort has recently been devoted to establish quantitative Mass spectrometry imaging (MSI) techniques[1,2,3,4,9,10,11,12]
Tumors are prone to imatinib resistance, which is mainly attributed to secondary somatic mutations in the receptor tyrosine kinases KIT (CD117 or stem cell factor receptor), the gene product of the protooncogene c-kit, or the platelet-derived growth factor receptor alpha (PDGFRA)[26,27]
We introduce generalized nonlinear regression as a superior calibration method based on imatinib-containing pixels, report matrix-assisted laser desorption/ionization (MALDI)-quantitative MSI (qMSI) of three full technical replicates, and compare these results [fast time of flight MALDI-TOF-qMSI and ultra-high-resolution Fourier-Transform Ion Cyclotron Resonance (FTICR-qMSI)] with conventional UPLC-ESI-QTOF-MS quantification
Summary
Www.nature.com/scientificreports much effort has recently been devoted to establish quantitative MSI (qMSI) techniques[1,2,3,4,9,10,11,12]. Advanced rational testing criteria for evaluating linearity of response, variability, reproducibility and limits of detection of qMSI have been suggested[13] Despite these technical advances, MALDI-qMSI has not yet been widely adapted to clinical pharmacology. Tumor heterogeneity and the poorly understood spatial organization of the tumor microenvironment present major challenges for drug uptake and, effective cancer treatment[15,16] This challenge has prompted qMSI studies of drug disposition and of pharmacological/toxic effects in tumor tissues and their surroundings in mice[17,18]. We present the first extensive clinical MALDI-qMSI drug disposition study of a TKI, imatinib, in 56 resection specimens of tumor and surrounding non-tumor tissues from 27 patients with the biopsy-proven rare disease gastrointestinal stromal tumor (GIST). We can demonstrate that independent of mutation status of the tumor, imatinib failed to penetrate or to be retained in tumor tissue in all GIST liver metastasis cases tested
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