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ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243569 | GEO | 2024/02/06

REPOSITORIES: GEO

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ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [scRNA-seq]

Project description: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.

2024-02-06 | GSE243562 | GEO

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [PDX RNA-seq]

2024-02-06 | GSE243564 | GEO

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [Cell Line ATAC-seq]

2024-02-06 | GSE243568 | GEO

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [Cell Line RNA-seq]

2024-02-06 | GSE243565 | GEO

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts

Project description:ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts

| PRJNA1018938 | ENA

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [scRNA-seq]

Project description:ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [scRNA-seq]

| PRJNA1018935 | ENA

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [PDX RNA-seq]

Project description:ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [PDX RNA-seq]

| PRJNA1018936 | ENA

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [Cell Line RNA-seq]

Project description:ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [Cell Line RNA-seq]

| PRJNA1018941 | ENA

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [Cell Line ATAC-seq]

Project description:ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts [Cell Line ATAC-seq]

| PRJNA1018942 | ENA

MERTK activation drives osimertinib resistance in EGFR-mutant non-small cell lung cancer.

Project description:Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.

| S-EPMC9337831 | biostudies-literature

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