Proteomic Reveals Reasons for Acquired Drug Resistance in Lung Cancer Derived Brain Metastasis Based on a Newly Established Multi-Organ Microfluidic Chip Model

Frontiers in Bioengineering and Biotechnology

Wenwen Liu¹  Qi Wang¹  Wenzhe Duan²  Shengkai Xia²  Song Wei²  Mingxin Xu²  Yingyan Wang³ 

[1] Cancer Translational Medicine Research Center, The Second Hospital, Dalian Medical University, Dalian, China;Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China;Laboratory Center for Diagnostics, Dalian Medical University, Dalian, China;

关键词: lung cancer;    brain metastasis;    microfluidic organ-on-a-chip;    drug resistance;    proteomic;   

DOI  :  10.3389/fbioe.2020.612091

来源: DOAJ

【 摘 要 】

Anti-tumor drugs can effectively shrink the lesions of primary lung cancer; however, it has limited therapeutic effect on patients with brain metastasis (BM). A BM preclinical model based on a multi-organ microfluidic chip has been established proficiently in our previous work. In this study, the BM subpopulation (PC9-Br) derived from the parental PC9 cell line was isolated from the chip model and found to develop obvious resistance to antineoplastic drugs including chemotherapeutic agents (cisplatin, carboplatin, pemetrexed) and tyrosine kinase inhibitors (TKIs) which target epidermal growth factor receptor (EGFR); this suggested that the acquisition of drug-resistance by brain metastatic cells was attributable to the intrinsic changes in PC9-Br. Hence, we performed proteomic and revealed a greatly altered spectrum of BM protein expression compared with primary lung cancer cells. We identified the hyperactive glutathione (GSH) metabolism pathway with the overexpression of various GSH metabolism-related enzymes (GPX4, RRM2, GCLC, GPX1, GSTM4, GSTM1). Aldehyde dehydrogenases (ALDH1A1, ALDH3A1) were also found to be upregulated in BM. What's more, loss of EGFR and phosphorylated EGFR in PC9-Br gave reasons for the TKIs resistance. Collectively, our findings indicated potential mechanisms for the acquirement of drug resistance occurred in BM, providing new strategies to overcome therapeutic resistance in lung cancer BM.

【 授权许可】

Unknown