从表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）向小细胞肺癌（SCLC）的组织学转化是EGFR酪氨酸激酶抑制剂（TKI）耐药的关键机制。然而，NSCLC 和转化 SCLC (t-SCLC) 之间的转录组变化仍未得到探索。我们通过对从 10 名患者（肺腺癌，22 名；组合 SCLC/ NSCLC，7；t-SCLC，30 个 ROI）。比较转化前和转化后肿瘤的转录组图谱和差异表达基因 (DEG)。EGFR-TKI 治疗后，93.7% (15/16) 的转化 SCLC (t-SCLC) 成分演变成神经内分泌高亚型（ SCLC-A 或 SCLC-N)。无论 EGFR-TKI 治疗和 EGFR 突变状态如何，都会发生向 t-SCLC 的转变，EGFR 表达在 mRNA 和蛋白质水平均显着下降 (P < 0.001)。通路分析显示，基因过度表达与 t-SCLC 的表观遗传改变有关。有趣的是，组蛋白脱乙酰酶 (HDAC) 抑制剂恢复了 SNU-2962A 细胞及其类器官模型中的 EGFR 表达。第三代EGFR-TKI奥希替尼和HDAC抑制剂芬匹司他的协同作用在体外和体内模型中得到验证。我们的研究表明，大多数t-SCLC表现出EGFR低表达的神经元亚型。 DEGs 分析和 t-SCLC 临床前模型确定表观遗传修饰剂是 t-SCLC 有前景的治疗策略。

Histological transformation from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored.We conducted whole transcriptome analysis of 59 regions of interest (ROIs) through the spatial profiling of FFPE tissues obtained from ten patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; t-SCLC, 30 ROIs). Transcriptomic profiles and differentially expressed genes (DEGs) were compared between pre- and post-transformed tumors.Following EGFR-TKI treatment, 93.7% (15/16) of transformed-SCLC (t-SCLC) components evolved into neuroendocrine-high subtypes (SCLC-A or SCLC-N). The transition to t-SCLC occurred regardless of EGFR-TKI treatment and EGFR mutational status, with a notable decrease in EGFR expression (P < 0.001) at both mRNA and protein levels. Pathway analysis revealed that gene overexpression was related to epigenetic alterations in t-SCLC. Interestingly, Histone deacetylase (HDAC) inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the HDAC inhibitor fimepinostat were validated in both in vitro and in vivo models.Our study demonstrated most t-SCLC showed neuronal subtypes with low EGFR expression. DEGs analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.