肺癌
突变体
癌症研究
转录组
细胞
癌症
生物
细胞生物学
医学
肿瘤科
遗传学
基因
基因表达
作者
Songji Oh,Jaemoon Koh,Tae Min Kim,Soyeon Kim,Jeonghwan Youk,Miso Kim,Bhumsuk Keam,Yoon Kyung Jeon,Ja‐Lok Ku,Dong‐Wan Kim,Doo Hyun Chung,Dae Seog Heo
标识
DOI:10.1158/1078-0432.c.7494055
摘要
<div>AbstractPurpose:<p>Histologic transformation from <i>EGFR</i>-mutant non–small cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored.</p>Experimental Design:<p>We conducted whole-transcriptome analysis of 59 regions of interest through the spatial profiling of formalin-fixed, paraffin-embedded tissues obtained from 10 patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; and t-SCLC, 30 regions of interests). Transcriptomic profiles and differentially expressed genes were compared between pre- and post-transformed tumors.</p>Results:<p>Following EGFR-TKI treatment, 93.7% (15/16) of 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 <i>EGFR</i> mutational status, with a notable decrease in EGFR expression (<i>P</i> < 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 inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the histone deacetylase inhibitor fimepinostat were validated in both <i>in vitro</i> and <i>in vivo</i> models.</p>Conclusions:<p>Our study demonstrated that most t-SCLC cases showed neuronal subtypes with low <i>EGFR</i> expression. Differentially expressed gene analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.</p></div>
科研通智能强力驱动
Strongly Powered by AbleSci AI