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| 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
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| 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.
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| 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.
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| Contributor(s) |
Hu B, Zhao D, Politi K |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Sep 19, 2023 |
| Last update date |
Feb 06, 2024 |
| Contact name |
Bomiao Hu |
| E-mail(s) |
bomiao.hu@yale.edu
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| Organization name |
Yale University
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| Street address |
310 Cedar Street
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| City |
New Haven |
| State/province |
CT |
| ZIP/Postal code |
06519 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (27)
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| GSM7791024 |
PC9EV, osimertinib, rep1 |
| GSM7791025 |
PC9EV, osimertinib, rep2 |
| GSM7791026 |
PC9EV, osimertinib, rep3 |
| GSM7791027 |
PC9ASCL1, vehicle, rep1 |
| GSM7791028 |
PC9ASCL1, vehicle, rep2 |
| GSM7791029 |
PC9ASCL1, vehicle, rep3 |
| GSM7791030 |
PC9ASCL1, osimertinib, rep1 |
| GSM7791031 |
PC9ASCL1, osimertinib, rep2 |
| GSM7791032 |
PC9ASCL1, osimertinib, rep3 |
| GSM7791033 |
HCC827EV, vehicle, rep1 |
| GSM7791034 |
HCC827EV, vehicle, rep2 |
| GSM7791035 |
HCC827EV, vehicle, rep3 |
| GSM7791036 |
HCC827EV, osimertinib, rep1 |
| GSM7791037 |
HCC827EV, osimertinib, rep2 |
| GSM7791038 |
HCC827EV, osimertinib, rep3 |
| GSM7791039 |
HCC827ASCL1, vehicle, rep1 |
| GSM7791040 |
HCC827ASCL1, vehicle, rep2 |
| GSM7791041 |
HCC827ASCL1, vehicle, rep3 |
| GSM7791042 |
HCC827ASCL1, osimertinib, rep1 |
| GSM7791043 |
HCC827ASCL1, osimertinib, rep2 |
| GSM7791044 |
HCC827ASCL1, osimertinib, rep3 |
| GSM7791045 |
HCC827ASCL1, persister, rep1 |
| GSM7791046 |
HCC827ASCL1, persister, rep2 |
| GSM7791047 |
HCC827ASCL1, persister, rep3 |
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| This SubSeries is part of SuperSeries: |
| GSE243569 |
ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts |
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| Relations |
| BioProject |
PRJNA1018941 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE243565_normalized.counts.xls.gz |
3.4 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
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