MUC1-C IS ESSENTIAL FOR INFLAMMATORY MEMORY OF TYROSINE KINASE INHIBITOR RESISTANCE IN NSCLC CELLS
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE294981 | GEO | 2025/04/22
REPOSITORIES: GEO
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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.
2025-04-02 | GSE263757 | GEO
Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities.
2022-04-06 | GSE193258 | GEO
Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities.
2022-04-06 | GSE193257 | GEO
Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities.
2022-04-06 | GSE193256 | GEO
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (pELS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at pELSs of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2022-06-21 | GSE206212 | GEO
Project description:Introduction: Overcoming of acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable obstacle for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are very complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR mutated lung cancer largely unknown. Methods: Osimertinib and afatinib-resistant EGFR-mutated lung cancer cells were established using by a stepwise method. Microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant NSCLC cells. Results: Microarray analysis was evaluated by bioinformatics analysis through medical-industrial collaboration. CRNDE and DGCR5 lncRNAs were highly expressed in EGFR-TKIs-resistant cells. CRNDE binds to eIF4A3 protein, down-regulates eIF4A3 and MUC1 expression, and down-regulates p-EGFR expression. CRNDE inhibition activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity and restored sensitivity to EGFR-TKIs. Conclusions: We identified lncRNA CRNDE associated with resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. CRNDE may be a novel therapeutic target for EGFR mutant NSCLC patients.
2021-04-28 | GSE163913 | GEO
Project description:Human non-small-cell lung cancers (NSCLCs) harboring activating mutations in epidermal growth factor receptor (EGFR) frequently respond to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib. However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency in EGFR-mutant NSCLCs. Here, we applied a genome-wide CRISPR-Cas9 screening to identify genetic determinants of EGFR TKI sensitivity and uncovered both known and putative candidates. Specifically, we show that knockout of RIC8A, a guanine nucleotide exchange factor (GEF) essential for G-alpha protein activation, enhanced EGFR TKI-induced cell death and prevented acquired resistance. Mechanistically, we demonstrate that RIC8A is a potent positive regulator of the pro-survival YAP signaling pathway, activation of which rescued the EGFR TKI sensitizing phenotype resulting from RIC8A knockout. We also show that knockout of ARIH2, or other components in the Cullin-5 E3 ubiquitin ligase complex, conferred resistance to EGFR inhibition, in part by promoting nascent protein synthesis through METAP2. Together, these data uncover a spectrum of previously unidentified regulators of EGFR TKI sensitivity in EGFR-mutant NSCLC cells, providing insights into the heterogeneity of EGFR TKI treatment responses in EGFR-mutant NSCLCs.
2019-11-14 | PXD014198 | Pride
Project description:Lung cancer continues to be the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are two 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance to it. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative proteomic and phosphoproteomic dataset to uncover alterations in signaling pathways, and to reveal a proteomic signature of EMT and kinases / phosphatases with altered protein expression and phosphorylation in the TKI resistant cells. We validated the significant role of SHP2 in the activation of RAS/MAPK and PI3K/AKT signaling pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified that dactolisib, a PI3K/mTOR inhibitor, in combination with osimertinib, may overcome osimertinib resistance both in vitro and in vivo. Introduction Lung cancer continues to be the leading cause of cancer mortality in the world (1). Many lung adenocarcinoma patients with activating epidermal growth factor receptor (EGFR) mutations initially respond dramaticlly to the first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). However, they eventually develop resistance. The most common mechanism of acquired resistance is the EGFR T790M gatekeeper site residue mutation (2). Osimertinib, a third generation irreversible EGFR TKI has been approved by the FDA to treat patients harboring the EGFR T790M mutation who have developed resistance to first- and second- generation EGFR TKIs (3). Recently, osimertinib was also approved for the front-line treatment of patients harboring EGFR mutations (4). Rociletinib is another irreversible inhibitor targeting the EGFR T790M mutation, which has minimal activity against wild-type EGFR. Both drugs have therapeutic benefits and have demonstrated activity in tumors with T790M-mediated resistance to other EGFR tyrosine kinase inhibitors (5, 6). Further development of rociletinib was ceased in 2016 due to less than expected efficacy, poor brain penetration leading to tumor progression in brain tissues and off-target effects on IGFR activation leading to hyperglycemia (7, 8). Although 3rd-generation TKIs provide clinical benefit to most patients with EGFR mutations, some patients, demonstrating primary resistance, still do not respond to these inhibitors. Complete responses are rare, and all patients eventually develop resistance, suggesting primary and acquired resistance mechanisms decrease the efficacy of the drugs (9, 10). Genomic approaches have been used primarily to interrogate osimertinib resistance mechanisms (9, 11-15). Several mechanisms of osimertinib resistance have been identified (16), including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events (17). However, the resistance mechanism is complex and still not fully understood. Previously, we have used SILAC-based quantitative phosphoproteomics to identify the global dynamic modification which occur upon treatment of TKI-sensitive and -resistant lung adenocarcinoma cells with the 1st and 2nd generation EGFR TKIs, erlotinib and afatinib. Utilizing this strategy, we identified the targets of mutant EGFR signaling pathways responsible for TKI resistance, and possible off-target effects of the drugs (18, 19). In this study, we employed SILAC-based quantitative mass spectrometry to characterize alterations in the proteome and phosphoproteome which occur upon acquired resistance and sought to identify novel mechanisms of resistance to the third generation EGFR TKIs, osimertinib and rociletinib. To our knowledge, this is the most comprehensive 3rd generation EGFR TKI resistant proteome and phosphoproteome analysis resource available to date.
2021-03-11 | PXD020108 | Pride
Project description:Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the acquired resistance to EGFR-TKIs, even third generation Osimertinib, the patients suffer poor prognosis. The resistance mechanisms are still not fully understood. Here, we demonstrate that increased expression of MUSASHI-2 (MSI2), an RNA binding protein, is novel mechanisms for resistance to EGFR-TKIs. We found that after long-exposure of gefitinib, the first generation EGFR-TKI, lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to not only gefitinib but also Osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the top list of the stemness-related genes upregulated in the EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including expression levels of Nanog a core stemness factor. We demonstrate that knockdown of MSI2 restored sensitivity to Osimertinib or gefitinib in the EGFR-TKI-resistant cells to the similar levels of the parental cells in vitro. RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to Osimertinib or gefitinib in parental cells. Finally, knockdown of MSI2 greatly increased sensitivity to Osimertinib in vivo. Collectively, our findings provide proof-of-principle that targeting MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent emergence of acquired resistance.
2021-08-27 | GSE168280 | GEO
Project description:Osimertinib, as a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved as a first-line therapy in advanced non–small-cell lung cancer (NSCLC) patients with EGFR-activating or T790M resistance mutations. However, the efficacy of osimertinib is limited due to acquired resistance. In order to search for the mechanism of resistance to osimertinib, we screened on significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells via RNA-sequence.In summary, our data elucidate the alterations in gene expression within lung cancer cells before and after resistance to osimertinib, aiding in the analysis and identification of key molecules influencing osimertinib resistance.
2024-03-30 | GSE262582 | GEO