Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer

Cell Death Dis. 2024 Aug 9;15(8):580. doi: 10.1038/s41419-024-06940-y.

Abstract

In EGFR-mutated lung cancer, the duration of response to tyrosine kinase inhibitors (TKIs) is limited by the development of acquired drug resistance. Despite the crucial role played by apoptosis-related genes in tumor cell survival, how their expression changes as resistance to EGFR-TKIs emerges remains unclear. Here, we conduct a comprehensive analysis of apoptosis-related genes, including BCL-2 and IAP family members, using single-cell RNA sequence (scRNA-seq) and spatial transcriptomics (ST). scRNA-seq of EGFR-mutated lung cancer cell lines captures changes in apoptosis-related gene expression following EGFR-TKI treatment, most notably BCL2L1 upregulation. scRNA-seq of EGFR-mutated lung cancer patient samples also reveals high BCL2L1 expression, specifically in tumor cells, while MCL1 expression is lower in tumors compared to non-tumor cells. ST analysis of specimens from transgenic mice with EGFR-driven lung cancer indicates spatial heterogeneity of tumors and corroborates scRNA-seq findings. Genetic ablation and pharmacological inhibition of BCL2L1/BCL-XL overcome or delay EGFR-TKI resistance. Overall, our findings indicate that BCL2L1/BCL-XL expression is important for tumor cell survival as EGFR-TKI resistance emerges.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Transgenic
  • Mutation* / genetics
  • Protein Kinase Inhibitors / pharmacology
  • RNA-Seq
  • Single-Cell Analysis*
  • Single-Cell Gene Expression Analysis
  • Transcriptome / genetics
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • ErbB Receptors
  • EGFR protein, human
  • Protein Kinase Inhibitors
  • bcl-X Protein