한빛사논문
- 조회74
Songji Oh1,2, Jaemoon Koh3, Tae Min Kim1,4,*, Soyeon Kim1,2, Jeonghwan Youk1,4, Miso Kim1,4, Bhumsuk Keam1,4, Yoon Kyung Jeon1,2,3, Ja-Lok Ku1,5, Dong-Wan Kim1,2,4, Doo Hyun Chung1,3, Dae Seog Heo1,4
1Cancer Research Institute, Seoul National University
2Integrated Major in Innovative Medical Science, Seoul National University College of Medicine
3Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine
4Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine
5Department of Biomedical Sciences, Seoul National University College of Medicine
S.O. and J.K. contributed equally to this work.
*Corresponding author: Tae Min Kim
Abstract
- Purpose: 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.
Experimental design: 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.
Results: 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.
Conclusions: 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.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-19)
- 국내 연구진
- 의약학 > 종양의학
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