Department of Thoracic Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510030, China.
Department of Thoracic Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, China; Shenzhen Clinical Medical College, Southern Medical University, Shenzhen,518101, China.
Eur J Pharm Sci. 2024 Aug 1;199:106805. doi: 10.1016/j.ejps.2024.106805. Epub 2024 May 18.
Drug resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a primary factor affecting their therapeutic efficacy in human non-small cell lung cancer (NSCLC). NSCLC cells can undergo epithelial-mesenchymal transition (EMT) induced by many factors in the tumour microenvironment (TME), which plays a crucial role in tumour drug resistance. In this study, a multicellular lung-on-a-chip that can realise the cell co-culture of the human non-small cell lung cancer cell line HCC827, human foetal lung fibroblasts (HFL-1), and human umbilical vein endothelial cells (HUVECs) is prepared. The TME was simulated on the chip combined with perfusion and other factors, and the drug evaluation of osimertinib was performed to explore the drug resistance mechanism of EGFR-TKIs. In the early stages, a two-dimensional static cell co-culture was achieved by microchip, and the results showed that HFL-1 cells could be transformed into cancer-associated fibroblasts (CAFs), and HCC827 cells could undergo EMT, both of which were mediated by Interleukin-6 (IL-6). Vimentin (VIM) and Alpha Skeletal Muscle Actin (a-SMA) expression of HFL-1 was upregulated, whereas E-cadherin (E-cad) expression of HCC827 was down-regulated. Further, N-cadherin (N-cad) expression of HCC827 was upregulated. In both the static cell co-culture and multicellular lung-on-a-chip, HCC827 cells with CAFs co-culture or IL-6 treatment developed resistance to osimertinib. Further use of the IL-6 antibody inhibitor tocilizumab could reverse EGFR-TKI resistance to a certain extent. Combination therapy with tocilizumab and EGFR-TKIs may provide a novel therapeutic strategy for overcoming EGFR-TKI resistance caused by EMT in NSCLC. Furthermore, the lung-on-a-chip can simulate complex TME and can be used for evaluating tumour resistance and exploring mechanisms, with the potential to become an important tool for personalised diagnosis, treatment, and biomedical research.
耐药性对不可逆的表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）是影响其在人类非小细胞肺癌（NSCLC）中的治疗效果的主要因素。肿瘤微环境（TME）中的许多因素可使 NSCLC 细胞发生上皮-间充质转化（EMT），这在肿瘤耐药中起着关键作用。在这项研究中，制备了一种能够实现人类非小细胞肺癌细胞系 HCC827、人胎肺成纤维细胞（HFL-1）和人脐静脉内皮细胞（HUVECs）共培养的多细胞肺芯片。该芯片结合灌注等因素模拟 TME，并进行奥希替尼的药物评价，以探讨 EGFR-TKIs 的耐药机制。在早期阶段，通过微芯片实现了二维静态细胞共培养，结果表明 HFL-1 细胞可转化为癌相关成纤维细胞（CAFs），HCC827 细胞可发生 EMT，这两者均由白细胞介素 6（IL-6）介导。HFL-1 的波形蛋白（VIM）和α-平滑肌肌动蛋白（a-SMA）表达上调，而 HCC827 的上皮钙黏蛋白（E-cad）表达下调。此外，HCC827 的 N-钙黏蛋白（N-cad）表达上调。在静态细胞共培养和多细胞肺芯片中，与 CAFs 共培养或用 IL-6 处理的 HCC827 细胞对奥希替尼产生耐药性。进一步使用白细胞介素 6 抗体抑制剂托珠单抗可在一定程度上逆转 EGFR-TKI 耐药性。托珠单抗和 EGFR-TKIs 的联合治疗可能为克服 NSCLC 中 EMT 引起的 EGFR-TKI 耐药提供一种新的治疗策略。此外，肺芯片可以模拟复杂的 TME，用于评估肿瘤耐药性并探索机制，有望成为个性化诊断、治疗和生物医学研究的重要工具。
