Introduction: Approximately 5% of patients with EGFR‐activating mutations acquire EGFR tyrosine kinase inhibitor (TKI) resistance through SCLC transformation. However, the reason for the poor outcome and the molecular basis of EGFR‐mutant SCLC that has transformed from adenocarcinoma remain unclear. Methods: In this study, we established two EGFR‐mutant SCLC cell lines from lung adenocarcinoma patients after failed EGFR‐TKI treatment to investigate their molecular basis and potential therapeutic strategies in the hope of improving patient outcome. Results: These two EGFR‐mutant SCLC cell lines displayed two different phenotypes: suspensive and adherent. Both phenotypes shared the same genomic alterations analyzed by array‐based comparative genomic hybridization assay. Increased expression of EGFR and mesenchymal markers and decreased expression of neuroendocrine markers were observed in adherent cells. Principal component analysis and hierarchical clustering analysis of RNA microarray revealed that these two cell lines displayed a unique gene expression pattern that was distinctly different from that in NSCLC and classical SCLC cells. Combined treatment using an EGFR‐TKI and an AKT inhibitor attenuated cell viabilities in our two cell lines. Moreover, the use of a histone deacetylase inhibitor significantly inhibited the cell viabilities of both cell lines in vitro and in vivo. Conclusion: Our findings suggest that EGFR‐mutant SCLC may be a distinct subclass of SCLC that exhibits epithelial‐mesenchymal transition phenotypes, and adding an AKT or histone deacetylase inhibitor to pre‐existing therapies may be one of the therapeutic choices for transformed EGFR‐mutant SCLC.

中文翻译：

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EGFR 突变型 SCLC 表现出异质性表型和对常见抗肿瘤药物的耐药性

简介：大约 5% 的 EGFR 激活突变患者通过 SCLC 转化获得 EGFR 酪氨酸激酶抑制剂 (TKI) 耐药。然而，从腺癌转化为 EGFR 突变型 SCLC 的结果不佳的原因和分子基础仍不清楚。方法：在本研究中，我们从 EGFR-TKI 治疗失败后的肺腺癌患者中建立了两个 EGFR 突变的 SCLC 细胞系，以研究它们的分子基础和潜在的治疗策略，以期改善患者的预后。结果：这两种 EGFR 突变的 SCLC 细胞系显示出两种不同的表型：悬浮和贴壁。通过基于阵列的比较基因组杂交分析，两种表型共享相同的基因组改变。在贴壁细胞中观察到 EGFR 和间充质标志物的表达增加以及神经内分泌标志物的表达减少。RNA微阵列的主成分分析和层次聚类分析表明，这两种细胞系显示出独特的基因表达模式，与NSCLC和经典SCLC细胞明显不同。使用 EGFR-TKI 和 AKT 抑制剂的联合治疗减弱了我们两个细胞系中的细胞活力。此外，组蛋白脱乙酰酶抑制剂的使用显着抑制了体外和体内两种细胞系的细胞活力。结论：我们的研究结果表明 EGFR 突变小细胞肺癌可能是小细胞肺癌的一个独特亚类，表现出上皮间质转化表型，