Fan Yan-Wen, Liu Mei-Hui, Xu Tao-Jun, Fan Ruo-Yue, Xiang Jing, Wu Jia-Qi, He Ming-Fang
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhu South Road, Nanjing, 211816, China.
Jiangsu Health Vocational College, Nanjing, China.
Med Oncol. 2025 Apr 21;42(5):167. doi: 10.1007/s12032-025-02718-0.
Small cell lung cancer (SCLC) is a type of high-grade neuroendocrine malignancy with low gene mutation. Chemotherapy is the major treatment strategy, but long-term clinical application often leads to drug resistance. Etoposide is a first-line drug approved by the US Food and Drug Administration for SCLC treatment, but etoposide-resistance is a problem. In this study, a SCLC cell line with etoposide-acquired resistance, H1048-ER, was constructed through a concentration gradient increasing method, and its resistance to etoposide was investigated in vitro and in a zebrafish model. Through transcriptome sequencing, real-time reverse transcription-quantitative polymerase chain reaction, and bioinformatic analyses of H1048-ER vs. H1048 cells, 51 differentially expressed genes were found to be significantly enriched in "collagen degradation" and "MET/FAK signaling activation in ECM". Among them, six genes (COL11A1, COL26A1, COL4A3, COL4A4, LAMA4, and LAMC1) had strong correlations with the prognosis of lung cancer. They may be key factors in the acquired etoposide resistance of H1048-ER cells. H1048-ER cells showed cross-resistance to cisplatin but were sensitive to doxorubicin and temozolomide. Our study provides novel insights into etoposide resistance in SCLC and affords the potential treatment options after etoposide resistance.
小细胞肺癌（SCLC）是一种基因突变率低的高级别神经内分泌恶性肿瘤。化疗是主要的治疗策略，但长期临床应用常导致耐药。依托泊苷是美国食品药品监督管理局批准用于治疗SCLC的一线药物，但依托泊苷耐药是一个问题。在本研究中，通过浓度梯度递增法构建了对依托泊苷获得性耐药的SCLC细胞系H1048-ER，并在体外和斑马鱼模型中研究了其对依托泊苷的耐药性。通过对H1048-ER与H1048细胞进行转录组测序、实时逆转录定量聚合酶链反应和生物信息学分析，发现51个差异表达基因在“胶原蛋白降解”和“细胞外基质中的MET/FAK信号激活”中显著富集。其中，6个基因（COL11A1、COL26A1、COL4A3、COL4A4、LAMA4和LAMC1）与肺癌预后密切相关。它们可能是H1048-ER细胞获得性依托泊苷耐药的关键因素。H1048-ER细胞对顺铂表现出交叉耐药，但对阿霉素和替莫唑胺敏感。我们的研究为SCLC中依托泊苷耐药提供了新的见解，并为依托泊苷耐药后的潜在治疗选择提供了依据。
