Targeting cancers with EGFR exon 20 insertion mutations by exploiting a dependency on parallel SRC signalling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA659244 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12513942.fastq.gz | Fastqsanger.gz | |||
| SRR12513942_1.fastq.gz | Fastqsanger.gz | |||
| SRR12513942_2.fastq.gz | Fastqsanger.gz | |||
| SRR12513943.fastq.gz | Fastqsanger.gz | |||
| SRR12513943_1.fastq.gz | Fastqsanger.gz |
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Project description:We performed RNAseq to compare differential gene expression between CUTO17, a human non-small cell lung cancer cell line which harbours an EGFR exon 20 insertion mutation, with CUTO17PozR, a cell line dervied from CUTO17 cells with acquired drug resistance to the EGFR inhibitor poziotinib through long-term drug exposure.
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Project description:Experimental aim: identification of SRC-2 and SRC-3-related genes in MCF-7 breast cancer cells. Experimental workflow: 1. shRNA transduction. MCF-7 cells were transduced with a mix of lentiviral particles containing five individual lentiviral pLKO.1-puro short hairpin (sh) RNA plasmids targeting different sequences on SRC-2 or SRC-3 mRNA and a pLKO.1-puro empty vector control. The puromycin selections were maintained for three weeks to obtain cells containing stably integrated shRNA. 2. Sample preparation. RNA was extracted from eight independent replicates expressing the pLKO.1-puro empty shRNA vector (shKTR), from eight replicates of SRC-2 shRNA expressing cells (shSRC-2), and from seven replicates of SRC-3 shRNA expressing cells (shSRC-3). 300 ng of total RNA from each cell sample was biotin-labelled and amplified.
2019-07-01 | E-MTAB-7018 | biostudies-arrayexpress
Project description:No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
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Project description:The non-receptor tyrosine kinase SRC is upregulated in various human cancers and plays crucial roles in cancer progression by promoting invasion and metastasis. We show that the transforming growth factor beta (TGF-β/SMAD pathway directly upregulates SRC during the epithelial-mesenchymal transition. In human epithelial MCF10A cells, TGF-β1 treatment markedly upregulated mRNA expression of SRC. Knockout of SMAD4 suppressed upregulation of SRC by TGF-β1. ChIP-sequencing analysis revealed that SRC was transcribed from the SRC1A promoter, which interacted with SMAD2 and SMAD4, in response to TGF-β1. These findings demonstrate that a direct interaction of the activated SMAD complex with the SRC1A promoter directly upregulates SRC and suggest that TGF-β contributes to SRC upregulation in the tumor microenvironment, where TGF-β-mediated tumor progression takes place.
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Project description:Chaetomium thermophilum plasmid insertion analysis
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Project description:The restoration of catalytic activity to mutant enzymes by small molecules is well-established for in vitro systems. Here we show that the protein tyrosine kinase Src R388A mutant can be rescued in live cells using the small molecule imidazole. Cellular rescue of a v-Src homolog was rapid and reversible and conferred predicted oncogenic properties. Using chemical rescue in combination with mass spectrometry, six known Src kinase substrates were confirmed, and several new protein targets identified. Chemical rescue data suggests that c-Src is active under basal conditions. Rescue of R388A c-Src also allowed contributions of Src to the MAP kinase pathway to be clarified. This chemical rescue approach is likely to be of broad utility in cell signaling. We were also interested in examining the impact of Src rescue on the kinetics of gene expression. Chronic gene expression changes in v-Src transformed colon cancer and NIH3T3 cells have been reported, but the chemical rescue method permits insights into rapid kinetic changes. We used gene microarray analysis of imidazole activated Src, 1 h after imidazole treatment of 8A7F cells as well as 6N7F control cells, a set of several genes show increases (>1.7-fold) at 1 h in the 8A7F cells and another set show decreases (>1.7-fold) at 1 h with minimal changes in 6N7F control cells. Thirteen of these genes were further analyzed using real-time RT-PCR and most of the genes tested showed similar changes using both techniques. These gene changes were not reported in cells chronically transformed with v-Src or rapidly stimulated with growth factors suggesting that rapid initiation of Src-mediated tyrosine phosphorylation may induce a specialized pattern of gene expression changes. However, these earlier experiments were done under different conditions which may also contribute to gene effects. Keywords: time course, cell type comparison
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Project description:Cells responding to DNA damage implement complex adaptive programs that often culminate in two distinct outcomes: apoptosis or senescence. Here, to systematically identify factors driving each response, we analyzed human IMR-90 fibroblasts exposed to increasing doses of the genotoxin etoposide. We identified SRC as a key kinase contributing to this decision fork. SRC was activated by low (50 μM) etoposide but not by high (200 μM) etoposide levels. At low DNA damage, SRC-mediated activation of p38 critically promoted cell survival and senescence, and increased pro-survival BCL2L2 levels, while SRC-mediated repression of p53 prevented a rise in pro-apoptotic PUMA levels. At high DNA damage, SRC was not active, leading to elevation of p53, inhibition of p38, and apoptosis. In mice exposed to DNA damage, pharmacologic inhibition of SRC prevented the tissue accumulation of senescent cells. Inhibiting SRC could be exploited for inducing senescent-cell apoptosis in tissues to improve health outcomes.
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Project description:To address the molecular mechanisms underlying c-Src-mediated tumor progression, we previously developed a model system using Csk-deficient fibroblasts that can be transformed by wild-type c-Src. In this study, we applied this system for the analysis of the potential contribution of miRNA to c-Src-mediated transformation. Pair-wise significance analysis of the microarray indicated that seven miR genes were significantly upregulated and six miRNA genes were downregulated in c-Src-transformed cells with a P value below 0.01 and with a fold change over 2.0. Csk-/- mouse embryonic fibroblasts (Csk-/- MEFs) were transfected with empty vector, c-Src, Csk/c-Src, or Csk. Each sample was run in duplicate.
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Project description:The rapidly growing family of coregulators of nuclear receptors includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have begun to emerge as important regulators of metabolic homeostasis, including the p160 Steroid Receptor Coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis in liver and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of SRC family members, we have performed targeted metabolomics analysis of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockout of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 knockout mice and their wild-type littermates in the fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC coactivator. Overall, we observed entire groups or subgroups of metabolites belonging to discrete metabolic pathways that were influenced in different tissues and/or feeding states due to ablation of individual SRC isoforms. Surprisingly, we identified very few metabolites that changed universally across the three SRC knockout models. These findings demonstrate that coactivator function has very limited redundancy even within the homologous SRC coactivator family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.
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