Citation: Guizhen Zhu, Yaoyao Zhao, Wenmei Zhang, Yuanyuan Wu, Yuanxing Liu, Guangsheng Guo, Xiayan Wang, Zhihong Liu. Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells[J]. Chinese Chemical Letters, ;2024, 35(2): 108466. doi: 10.1016/j.cclet.2023.108466 shu

Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells

Guizhen Zhu ^a ,
Yaoyao Zhao ^{a, *,} ,
Wenmei Zhang ^a ,
Yuanyuan Wu ^a ,
Yuanxing Liu ^a ,
Guangsheng Guo ^{a, b} ,
Xiayan Wang ^a ,
Zhihong Liu ^{c, *,}

a.
Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China
b.
Minzu University of China, Beijing 100081, China
c.
Key Laboratory for the Synthesis and Application of Organic Functional Molecules, College of Health Science and Engineering, Hubei University, Wuhan 430062, China

zhaoyaoyao@bjut.edu.cn

zhhliu@whu.edu.cn

Received Date: 9 March 2023
Revised Date: 23 March 2023
Accepted Date: 16 April 2023
Available Online: 21 April 2023

Figures(6)

Patients with epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) often show primary resistance to gefitinib therapy. It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors. Herein, we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry (sDMH-scMS) by integrating living-cell electrolaunching ionization MS (ILCEI-MS) and high-performance liquid chromatography-MS (HPLC-MS) analysis, and the primary resistance of NSCLC cells to gefitinib was studied using this platform. The ILCEI-MS analysis showed that approximately 11.9% of NSCLC single cells contained the gefitinib metabolite M11; HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells. The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells, and the intensity of gefitinib metabolites was significantly higher than in PC9 cells, suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism. Moreover, the combination of gefitinib and the drug-metabolizing enzyme inhibitor α-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells. Overall, the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.
- Single-cell mass spectrometry,
- Drug metabolism,
- Non-small cell lung cancer,
- Gefitinib,
- Primary resistance
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