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Published on: August 24, 2017
Transcriptomic Heterogeneity of EGFR-Mutant Non-Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer
Songji Oh1,2, Jaemoon Koh3, Tae Min Kim1,4
1Cancer Research Institute, Seoul National University, Seoul, South Korea.
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.
Insights
Histologic transformation to small-cell lung cancer (SCLC) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKI). Epigenetic modifiers show promise for treating transformed SCLC with low EGFR expression.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Histologic transformation from EGFR-mutant non-small cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) is a primary resistance mechanism to EGFR tyrosine kinase inhibitors (TKI).
- Transcriptomic alterations during this transformation remain largely unexplored, hindering the development of targeted therapies.
Purpose of the Study:
- To investigate the transcriptomic changes associated with the histologic transformation of EGFR-mutant NSCLC to SCLC.
- To identify potential therapeutic targets for TKI-resistant, transformed SCLC.
Main Methods:
- Whole-transcriptome analysis using spatial profiling of formalin-fixed, paraffin-embedded tissues from NSCLC and transformed SCLC (t-SCLC) patient samples.
- Comparison of transcriptomic profiles and differentially expressed genes between pre- and post-transformed tumors.
- In vitro and in vivo validation of identified therapeutic strategies using cell lines and organoid models.
Main Results:
- The majority of t-SCLC components (93.7%) exhibited neuroendocrine-high subtypes (SCLC-A or SCLC-N) following EGFR-TKI treatment.
- Transformation to t-SCLC occurred independently of EGFR-TKI treatment and EGFR mutational status, with significantly decreased EGFR expression at both mRNA and protein levels.
- Pathway analysis indicated that gene overexpression in t-SCLC was linked to epigenetic alterations, and histone deacetylase inhibitors restored EGFR expression.
Conclusions:
- Most t-SCLC cases display neuronal subtypes characterized by low EGFR expression.
- Epigenetic modifiers represent a promising therapeutic strategy for TKI-resistant transformed SCLC, as identified through differential gene expression analysis and preclinical models.
