journal contribution posted on 2023-04-03, 18:40 authored by Hitomi Jo, Shigehiro Yagishita, Yoshiharu Hayashi, Shoraku Ryu, Mikiko Suzuki, Shinji Kohsaka, Toshihide Ueno, Yuji Matsumoto, Hidehito Horinouchi, Yuichiro Ohe, Shun-ichi Watanabe, Noriko Motoi, Yasushi Yatabe, Hiroyuki Mano, Kazuhisa Takahashi, Akinobu Hamada
Supplementary Figure 1
The spectra and annotations of fragment ions from pure test drugs of afatinib, gefitinib, osimertinib, poziotinib, brigatinib, crizotinib, entrectinib, and lorlatinib are shown.
Japan Agency for Medical Research and Development
Cyclic Innovation for Clinical Empowerment
AMED Research on Regulatory Science of Pharmaceuticals and Medical Devices
National Cancer Center Research and Development Fund
ARTICLE ABSTRACTPatient-derived xenografts (PDX) can adequately reflect clinical drug efficacy. However, the methods for evaluating drug efficacy are not fully established. We selected five non–small cell lung cancer (NSCLC) PDXs with genetic alterations from established PDXs and the corresponding molecular targeted therapy was administered orally for 21 consecutive days. Genetic analysis, measurement of drug concentrations in blood and tumors using LC/MS-MS, and analysis of drug distribution in tumors using matrix-assisted laser desorption/ionization mass spectrometry were performed. Fifteen (20%) PDXs were established using samples collected from 76 patients with NSCLC with genetic alterations. The genetic alterations observed in original patients were largely maintained in PDXs. We compared the drug efficacy in original patients and PDX models; the efficacies against certain PDXs correlated with the clinical effects, while those against the others did not. We determined blood and intratumor concentrations in the PDX model, but both concentrations were low, and no evident correlation with the drug efficacy could be observed. The intratumoral spatial distribution of the drugs was both homogeneous and heterogeneous for each drug, and the distribution was independent of the expression of the target protein. The evaluation of drug efficacy in PDXs enabled partial reproduction of the therapeutic effect in original patients. A more detailed analysis of systemic and intratumoral pharmacokinetics may help clarify the mode of action of drugs. Further development of evaluation methods and indices to improve the prediction accuracy of clinical efficacy is warranted.