Drug tolerant persisters in erlotinib treated EGFR-mutated lung adenocarcinoma arise from pre-existing tumor cells and survive in an adapted stromal microenvironment

Targeted therapies require life-long treatment, as drug discontinuation invariably leads to tumor recurrence. Recurrence is thought to mainly be driven by minor subpopulations of drug tolerant persister (DTP) cells that survive the cytotoxic drug effect. In lung cancer, DTP studies have mainly been conducted using tumor cell line models. We conducted an in vivo DTP study using a lung adenocarcinoma (LUAD) patient-derived xenograft (PDX) tumor driven by an epidermal growth factor receptor (EGFR) mutation. Daily treatment of tumor-bearing mice for 5-6 weeks markedly shrunk the tumors and generated DTPs, which were analyzed by bulk population transcriptome. Microarray transcriptome profiling was performed on 4 baseline (BL) and 4 DTP tumors; total RNAs from xenografts were amplified by DASL kit and hybridized to Illumina HT12v4 chip

靶向治疗需终身维持给药，因为停药后必然会引发肿瘤复发。目前学界认为，肿瘤复发主要由耐受治疗的持久细胞（drug tolerant persister, DTP）这一少数亚群驱动，这类细胞可在细胞毒性药物的作用下存活。在肺癌领域，现有DTP相关研究多以肿瘤细胞系为模型开展。本研究采用表皮生长因子受体（epidermal growth factor receptor, EGFR）突变驱动的肺腺癌（lung adenocarcinoma, LUAD）患者来源异种移植（patient-derived xenograft, PDX）模型，开展了体内DTP研究。对荷瘤小鼠每日给药5~6周后，肿瘤显著缩小并生成了DTP，随后通过群体转录组对这些细胞进行分析。本研究对4例基线（baseline, BL）肿瘤样本与4例DTP肿瘤样本开展了微阵列转录组谱分析：将异种移植瘤提取的总RNA通过DASL试剂盒进行扩增后，与Illumina HT12v4芯片进行杂交。