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Updated: Jun 17, 2025
Detection of Rare Mutations in CtDNA Using Next Generation Sequencing
Published on: August 24, 2017
Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression
Motohiro Izumi1, Masanori Fujii1, Ikei S Kobayashi1
1Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
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.
Insights
Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer involves changes in apoptosis genes. Upregulation of BCL2L1/BCL-XL in tumor cells promotes survival, suggesting it as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Acquired resistance limits tyrosine kinase inhibitor (TKI) efficacy in EGFR-mutated lung cancer.
- Apoptosis-related genes are vital for tumor cell survival, but their role in acquired resistance is not fully understood.
Purpose of the Study:
- To comprehensively analyze changes in apoptosis-related gene expression during the emergence of EGFR-TKI resistance.
- To investigate the role of BCL2L1/BCL-XL in EGFR-TKI resistance and explore therapeutic strategies.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of lung cancer cell lines and patient samples.
- Spatial transcriptomics (ST) analysis in a mouse model of EGFR-driven lung cancer.
- Genetic ablation and pharmacological inhibition of BCL2L1/BCL-XL.
Main Results:
- EGFR-TKI treatment led to BCL2L1 upregulation in EGFR-mutated lung cancer cells.
- BCL2L1 was highly expressed in tumor cells, while MCL1 was lower compared to non-tumor cells.
- Genetic or pharmacological inhibition of BCL2L1/BCL-XL overcame or delayed EGFR-TKI resistance.
Conclusions:
- BCL2L1/BCL-XL plays a critical role in tumor cell survival during acquired EGFR-TKI resistance.
- Targeting BCL2L1/BCL-XL represents a potential therapeutic strategy to overcome resistance in EGFR-mutated lung cancer.
