Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA736433 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14770051_1.fastq.gz | Fastqsanger.gz | |||
| SRR14770051_2.fastq.gz | Fastqsanger.gz | |||
| SRR14770052_1.fastq.gz | Fastqsanger.gz | |||
| SRR14770052_2.fastq.gz | Fastqsanger.gz | |||
| SRR14770053_1.fastq.gz | Fastqsanger.gz |
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Project description:MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory responseThe oncogenic MUC1-C protein functions as a master regulator of NSCLC cell resistance to osimertinib by unclear mechanisms. We report that MUC1-C-mediated regulation of STAT1 and the interferon (IFN) type I/II pathways is necessary for establishing osimertinib resistance. Studies of osimertinib-resistant NSCLC cells selected for growth in the absence of drug further demonstrate that revertant cells are dependent on MUC1-C for recalling resistance to osimertinib. We show that establishing and recalling osimertinib resistance is dependent on activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1 and PBAF. The MUC1 pELS regions function as memory domains for activation of MUC1-C and downstream STAT1 and IFN stimulated genes in conferring osimertinib resistance. Of clinical relevance, we report that the MUC1-C-driven inflammatory responses are induced in patient-derived, osimertinib-resistant MGH170 NSCLC cells with MET amplification. Our results further demonstrate that MGH170 cells are dependent on the MUC1-C-induced inflammatory response for resistance to the osimertinib and combination of osimertinib with the MET inhibitor capmatinib. These findings indicate that MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory response.
2025-06-26 | GSE270997 | GEO
Project description:MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory responseThe oncogenic MUC1-C protein functions as a master regulator of NSCLC cell resistance to osimertinib by unclear mechanisms. We report that MUC1-C-mediated regulation of STAT1 and the interferon (IFN) type I/II pathways is necessary for establishing osimertinib resistance. Studies of osimertinib-resistant NSCLC cells selected for growth in the absence of drug further demonstrate that revertant cells are dependent on MUC1-C for recalling resistance to osimertinib. We show that establishing and recalling osimertinib resistance is dependent on activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1 and PBAF. The MUC1 pELS regions function as memory domains for activation of MUC1-C and downstream STAT1 and IFN stimulated genes in conferring osimertinib resistance. Of clinical relevance, we report that the MUC1-C-driven inflammatory responses are induced in patient-derived, osimertinib-resistant MGH170 NSCLC cells with MET amplification. Our results further demonstrate that MGH170 cells are dependent on the MUC1-C-induced inflammatory response for resistance to the osimertinib and combination of osimertinib with the MET inhibitor capmatinib. These findings indicate that MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory response.
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Project description:MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory responseThe oncogenic MUC1-C protein functions as a master regulator of NSCLC cell resistance to osimertinib by unclear mechanisms. We report that MUC1-C-mediated regulation of STAT1 and the interferon (IFN) type I/II pathways is necessary for establishing osimertinib resistance. Studies of osimertinib-resistant NSCLC cells selected for growth in the absence of drug further demonstrate that revertant cells are dependent on MUC1-C for recalling resistance to osimertinib. We show that establishing and recalling osimertinib resistance is dependent on activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1 and PBAF. The MUC1 pELS regions function as memory domains for activation of MUC1-C and downstream STAT1 and IFN stimulated genes in conferring osimertinib resistance. Of clinical relevance, we report that the MUC1-C-driven inflammatory responses are induced in patient-derived, osimertinib-resistant MGH170 NSCLC cells with MET amplification. Our results further demonstrate that MGH170 cells are dependent on the MUC1-C-induced inflammatory response for resistance to the osimertinib and combination of osimertinib with the MET inhibitor capmatinib. These findings indicate that MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory response.
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Project description:Exosomal miRNAs involved in resistance to osimertinib in EGFR-mutant NSCLC cells were successfully identified through the microoarray analysis.
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Project description:Aberrant epigenetic regulation is closely associated with drug tolerance, an early step in the acquisition of drug resistance. We previously reported that a pioneer transcriptional factor (also called an epigenetic initiator) rapidly induced by osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, plays a pivotal role in promoting the formation of osimertinib-tolerant cells. In this study, to identify novel epigenetic factors associated with osimertinib-tolerance, we performed a comprehensive screening of epigenetic factors whose expression is rapidly induced by osimertinib. Our results revealed that HDAC5, a class IIa histone deacetylase (HDAC), is the most prominently induced epigenetic factor in EGFR-mutant non-small cell lung cancer (NSCLC) cell lines during the early response to osimertinib. Knockdown of HDAC5 significantly reduced the emergence of osimertinib-resistant cells. Furthermore, treatment with LMK235, a selective HDAC5 inhibitor, significantly increased global histone acetylation and enhanced osimertinib-induced apoptosis. These findings underscore the potential of HDAC5 as a novel therapeutic target to overcome osimertinib-resistance and propose LMK235 as a promising compound to provide significant therapeutic benefits for EGFR-mutant NSCLC patients undergoing osimertinib treatment.
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