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Series GSE243565 Query DataSets for GSE243565
Status Public on Feb 06, 2024
Title ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [Cell Line RNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKIs). However, most of these responses are partial with drug tolerant residual disease remaining even at the time of maximal response. This residual disease ultimately leads to relapses which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the 3rd generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally, but not mutationally, distinct from bulk pre-treatment tumor. Using single cell transcriptional profiling we found evidence of cells matching the profiles of drug-tolerant cells present in the pre-treatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, we found that ASCL1 confers drug tolerance by initiating an epithelial-to-mesenchymal gene expression program in permissive cellular contexts. Our study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment and explains why specific phenotypes are only observed in certain tumors.
Overall design Human lung cancer cell lines stably transfected with EV or dox-inducible ASCL1 were treated with vehicle or osimertinib for different length of time. The gene expression of the resulting cells were profiled by RNA-seq.
Contributor(s) Hu B, Zhao D, Politi K
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Submission date Sep 19, 2023
Last update date Feb 06, 2024
Contact name Bomiao Hu
Organization name Yale University
Street address 310 Cedar Street
City New Haven
State/province CT
ZIP/Postal code 06519
Country USA
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (27)
GSM7791021 PC9EV, vehicle, rep1
GSM7791022 PC9EV, vehicle, rep2
GSM7791023 PC9EV, vehicle, rep3
This SubSeries is part of SuperSeries:
GSE243569 ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
BioProject PRJNA1018941

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Supplementary file Size Download File type/resource
GSE243565_normalized.counts.xls.gz 3.4 Mb (ftp)(http) XLS
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Raw data are available in SRA

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