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

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.