Transcriptomic Heterogeneity of EGFR-Mutant Non-Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer.

IF 10 1区 医学 Q1 ONCOLOGY
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
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Abstract

Purpose: Histologic transformation from 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 (TKI). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored.

Experimental design: 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.

Results: 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 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 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 in vitro and in vivo models.

Conclusions: Our study demonstrated that most t-SCLC cases showed neuronal subtypes with low EGFR expression. Differentially expressed gene analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.

表皮生长因子受体突变的非小细胞肺癌向小细胞肺癌演变的转录组异质性。
目的:从表皮生长因子受体(EGFR)突变的非小细胞肺癌(NSCLC)到小细胞肺癌(SCLC)的组织学转化是表皮生长因子受体酪氨酸激酶抑制剂(TKIs)耐药的关键机制。然而,NSCLC和转化的SCLC(t-SCLC)之间的转录组变化仍未得到探索:实验设计:我们通过对10名患者(肺腺癌,22例;合并SCLC/NSCLC,7例;t-SCLC,30例)的FFPE组织进行空间图谱分析,对59个感兴趣区(ROIs)进行了全转录组分析。对转化前和转化后肿瘤的转录组图谱和差异表达基因(DEGs)进行了比较:结果:表皮生长因子受体抑制剂-TKI治疗后,93.7%(15/16)的转化型SCLC(t-SCLC)成分演变为神经内分泌高亚型(SCLC-A或SCLC-N)。向t-SCLC的转变与表皮生长因子受体-TKI治疗和表皮生长因子受体突变状态无关,表皮生长因子受体的表达在mRNA和蛋白质水平均显著下降(P < 0.001)。通路分析显示,基因过表达与t-SCLC的表观遗传学改变有关。有趣的是,组蛋白去乙酰化酶(HDAC)抑制剂能恢复 SNU-2962A 细胞及其类器官模型中表皮生长因子受体的表达。第三代表皮生长因子受体抑制剂osimertinib和HDAC抑制剂fimepinostat的协同作用在体外和体内模型中均得到了验证:我们的研究表明,大多数t-SCLC表现为EGFR低表达的神经元亚型。DEGs分析和t-SCLC临床前模型确定了表观遗传修饰剂是治疗t-SCLC的一种有前景的策略。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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