Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA284924 | ENA |
REPOSITORIES: ENA
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Project description:RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore anti-tumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell cycle arrest at G0/G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong anti-tumor effect of dovitinib was observed in LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene set enrichment analysis of gene expression and receptor tyrosine kinase assay revealed that Src, a central gene in focal adhesion , was activated in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src. To identify potential mechanisms of acquired resistance to dovitinib, we established LC-2/ad DR cells with acquired resistance to dovitinib by exposing LC-2/ad cells to increasing doses of dovitinib. LC-2/ad DR cells showed strong resistance to dovitinib (IC50> 3 μmol/L). Next, LC-2/ad and LC-2/ad DR cells were subjected to genome-wide gene expression profiling using cDNA microarray.
2015-09-01 | E-GEOD-69226 | biostudies-arrayexpress
Project description:RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore anti-tumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell cycle arrest at G0/G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong anti-tumor effect of dovitinib was observed in LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene set enrichment analysis of gene expression and receptor tyrosine kinase assay revealed that Src, a central gene in focal adhesion , was activated in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.
2015-09-01 | GSE69226 | GEO
Project description:Acquired drug resistance is the major therapeutic obstacle to maintenance treatment of advanced-stage non-small cell lung cancer. Lung adenocarcinoma (ADC) harboring driver mutations also showed poor response to immune checkpoint inhibitors (ICIs). Underlying mechanisms of how drug insensitivity evolves remain unclear. Here we explored the intratumoral heterogeneity of tyrosine kinase inhibitor (TKI)-resistant anaplastic lymphoma kinase (ALK)-rearranged lung ADC organoids using single-cell RNA-sequencing (scRNA-seq) transcriptomic analysis. IL-17 signaling pathway was found highly induced in a subpopulation of pre-existing ALK-TKI-resistant cells. These drug-tolerant persister (DTP) cells, also found to have high surface intracellular adhesion molecule 1 (ICAM-1) expression level, were more resistant towards ALK-TKI and expressed a higher level of cancer-stem cell transcriptional factors. Moreover, tumor cells with high ICAM-1 expression were found spatially correlated with RORɣt+ Th17 infiltration in ALK-rearranged NSCLC resected tumor tissues. In conclusion, our data revealed marked intratumoral heterogeneity in ALK-rearranged tumor, and pre-existing DTP cells may contribute to the development of drug insensitivity in ALK-rearranged lung ADC.
2023-08-09 | GSE223779 | GEO
Project description:The model is based on publication:
Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification
Abstract:
Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
2019-09-30 | BIOMD0000000827 | BioModels
Project description:RET expression is upregulated in AML subtypes harboring genetic fusions of MLL-1 genes compared to age-matched healthy donors and other AML subtypes. In addition, we identify a novel epigenetic mechanism of RET overexpression in MLL-rearranged AML.
2024-03-04 | GSE241738 | GEO
Project description:We examined microarray data of miRNAs and mRNAs from 77 cases of lung adenocarcinoma, including 42 ALK-rearranged cases. a multistep bioinformatics approach to build a miRNA–mRNA regulatory network in ALK-rearranged lung adenocarcinoma.
2022-03-14 | GSE128310 | GEO
Project description:We examined microarray data of miRNAs and mRNAs from 77 cases of lung adenocarcinoma, including 42 ALK-rearranged cases. a multistep bioinformatics approach to build a miRNA–mRNA regulatory network in ALK-rearranged lung adenocarcinoma.
2022-03-14 | GSE128309 | GEO
Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
2019-09-21 | E-MTAB-8340 | biostudies-arrayexpress
Project description:With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Additionally, we have detected upregulated expression of MET and RET transcripts in SCNPC metastases relative to adenocarcinoma. Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits MET, RET and VEGFR2, on SCNPC patient-derived xenografts (PDX) in vivo. Surveillance of SU2C and University of Washington rapid autopsy mCRPC cohorts through RNA-Seq revealed that increased MET expression significantly correlated with loss of AR expression and activity. In vitro treatment of SCNPC PDX cells with AMG 337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability in LuCaP 93, but not in LuCaP 173.1. Notably, tumor volume was significantly decreased (p<0.001) with cabozantinib treatment in SCID mice bearing LuCaP 93 and LuCaP 173.1 tumors. Tissue analysis indicated that tumor cell proliferation was not inhibited by cabozantinib, but that cabozantinib decreased microvessel density (CD31) in LuCaP 93 (p<0.001) and LuCaP 173.1 (p<0.01) tumors. RNA-Seq and gene set enrichment analysis determined that hypoxia and glycolysis pathways were increased in cabozantinib treated tumors relative to control tumors. Thus, cabozantinib inhibited tumor growth in MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumors in vivo and this activity was independent of MET or RET expression in LuCaP 173.1. Our data suggest that the most likely mechanism of tumor growth suppression is through disruption of the stromal architecture and cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.
2021-01-27 | GSE148538 | GEO
Project description:LKB1 deficiency in lung adenocarcinoma (LUAD) leads to primary resistance to immune checkpoint inhibitors. However, the underlying molecular mechanism remains unclear. Here, we showed that LKB1 deficiency significantly affected the tumor immune landscape by decreasing the infiltration of most immunocyte populations and downregulating the expression of intercellular adhesion molecule-1 (ICAM1). LKB1 deficiency promoted cancer evasion due to loss of ICAM1-mediated antitumor immunity, including immune-competent cell cytotoxicity and tumor infiltration. CDK4/6 inhibitors reversed this process in a targeted manner. A tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies slowed tumor growth and increased survival in syngeneic mouse models of LKB1-deficient lung adenocarcinoma. Combining a CDK4/6 inhibitor, which is clinically approved, with PD-1 blockade therapy is thus a promising option for lung adenocarcinoma patients harboring LKB1 mutations.
2022-12-16 | GSE182228 | GEO