Data from Transcriptomic Heterogeneity of <i>EGFR</i>-Mutant Non–Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer

<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>