Tumor-independent host gene expression changes induced by tyrosine kinase inhibitors
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ABSTRACT:
PROVIDER: PRJNA446647 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptome analysis was used to identify tumor-independent changes after treatment with different tyrosine kinase inhibitors (TKIs).
2018-03-29 | GSE112466 | GEO
Project description:Host-dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors
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Project description:Tyrosine Kinase Inhibitor Cardiotoxicity
| PRJNA352077 | ENA
Project description:Using a three-pronged MS-based proteomic approach, we assessed the mode-of-action of four clinically-relevant tyrosine kinase inhibitors in an epithelial cancer cell line. Here we defined the: (I) semi-quantitative tyrosine kinome; (II) drug interactome; and (III) drug-induced effects on the tyrosine signalome. We first examined the entire proteome and kinome profile expressed in the A431 cell line, and determined the relative abundance of all possible protein targets of the tyrosine kinase inhibitors. We therefore utilized a ‘shot-gun’ approach that involved a multidimensional separation-based proteomic strategy. To ensure maximal protein identification, we reduced sample complexity by strong cation exchange (SCX) chromatography, and analyzed all fractions by LC-MS/MS. To determine the direct targets of the four selected TKIs, we subjected the proteins extracted from the A431 cancer cell line to drug-coupled affinity matrices. By comparing the pull-down results from a lysate with a second identical lysate to which 20 uM of the inhibitor had been added to block binding to the beads, we were able to identify selective binding interactors using LC-MS/MS. This differential affinity pull-downs approach allowed us to also quantitatively evaluate the binding affinity of the tyrosine kinases to each of the drugs. To evaluate the global tyrosine phosphorylation dynamics that occurs in A431 cells upon treatment with each of the four inhibitors, phosphotyrosine peptides were enriched and identified by quantitative mass spectrometry. For this purpose, we treated the cells with each inhibitor for 2 h at appropriate concentrations adopted from reported studies. Cells were lysed, and the proteins digested with the proteases Lys-C and trypsin. To allow quantitation of the phosphorylated peptides originating from the three different peptide pools (control/imatinib/dasatinib or control/bosutinib/nilotinib), we used stable isotope dimethyl labeling. Subsequently, tyrosine-phosphorylated peptides were enriched by immunoprecipitation and analyzed by LC-MS/MS.
2014-05-12 | PXD000681 | Pride
Project description:To define molecular markers of tyrosine kinase inhibitor-induced cardiotoxicity, we measured transcriptome changes in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with one of four tyrosine kinase inhibitors (Erlotinib, Lapatinib, Sorafenib, or Sunitinib) displaying a range of mild to severe cardiotoxicity or a vehicle-only control (DMSO). Gene expression changes were assessed at the cell population level using total RNA-seq, which measured levels of both mRNAs and non-coding RNAs. hiPSC-CMs used in this study were the Cor.4U cells purchased from Ncardia.
2019-03-23 | GSE114686 | GEO
Project description:Tyrosine kinase activity is the crucial enzymatic activity driving all known functions of the BCR-ABL protein and is required for protection from apoptosis by BCR-ABL, therefore, targeting this enzyme is an effective approach for therapeutic strategies. Recently, a novel structural entity, imatinib (STI571; Novartis, Basel, Switzerland), a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL, has shown promise against Ph-positive leukemia in human clinical trials. However, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for overriding chemotherapy to eradicate this disease. AMN107 and BMS-354825 are clinically active “next-generation” BCR-ABL inhibitors. One potentially powerful approach is to use these compounds in combination with imatinib. The rationale for such approaches is that an inhibitor cocktail may target the widest range of resistant clones and thereby delay the onset of acquired drug resistance. More potent BCR-ABL inhibitors would be to target residual leukemia that persists in patients in whom imatinib induces durable remission but failed to eradicate the disease. From these points, our studies are performed to determine (1) the differences of molecular signaling pathways between BMS-354825 and imatinib (2) the mechanisms by which drug resistance of BMS-354825 and imatinib occur except for point mutation of BCR-ABL kinase domain. Keywords: drug sensitivity
2006-03-31 | GSE2810 | GEO
Project description:mTOR is a serine/threonine kinase with a crucial role in regulating fundamental cellular processes and is an attractive anticancer target. Multiple clinical trials of mTOR kinase inhibitors such as AZD2014 that suppress both mTORC1 and mTORC2 are ongoing, but their specificity and toxicity features remain a concern. We have developed an inducible kinase-dead D2338A mTOR mouse knock-in model and show that it is useful to study the kinase-independent function of mTOR and for assessing the off-target effects of mTOR kinase inhibitors. We found that while the mTOR KI mice in hematopoietic system displayed similar phenotypes to that of mTOR KO mice, they have significantly prolonged survival time than the KO mice. Whereas AZD2014 was mostly on-target in suppressing mTOR kinase activity, mimicking that seen in KI stem cells in transcriptome analysis, off-target genes in KI cells induced by AZD2014 including Ahnak2, Emp1, Lilrb4, Tpsb2, and Cma1 were detected. Our studies reveal kinase-independent function of mTOR in hematopoiesis and presents a mouse model for precisely assessing specificity of mTOR kinase inhibitors. Stringent test of drugs with such mouse models in the preclinical setting may provide useful information guiding the safety and efficacy of related clinical trials.
2023-08-29 | GSE172248 | GEO
Project description:mTOR is a serine/threonine kinase with a crucial role in regulating fundamental cellular processes and is an attractive anticancer target. Multiple clinical trials of mTOR kinase inhibitors such as AZD2014 that suppress both mTORC1 and mTORC2 are ongoing, but their specificity and toxicity features remain a concern. We have developed an inducible kinase-dead D2338A mTOR mouse knock-in model and show that it is useful to study the kinase-independent function of mTOR and for assessing the off-target effects of mTOR kinase inhibitors. We found that while the mTOR KI mice in hematopoietic system displayed similar phenotypes to that of mTOR KO mice, they have significantly prolonged survival time than the KO mice. Whereas AZD2014 was mostly on-target in suppressing mTOR kinase activity, mimicking that seen in KI stem cells in transcriptome analysis, off-target genes in KI cells induced by AZD2014 including Ahnak2, Emp1, Lilrb4, Tpsb2, and Cma1 were detected. Our studies reveal kinase-independent function of mTOR in hematopoiesis and presents a mouse model for precisely assessing specificity of mTOR kinase inhibitors. Stringent test of drugs with such mouse models in the preclinical setting may provide useful information guiding the safety and efficacy of related clinical trials.
2023-08-30 | GSE172247 | GEO
Project description:mTOR is a serine/threonine kinase with a crucial role in regulating fundamental cellular processes and is an attractive anticancer target. Multiple clinical trials of mTOR kinase inhibitors such as AZD2014 that suppress both mTORC1 and mTORC2 are ongoing, but their specificity and toxicity features remain a concern. We have developed an inducible kinase-dead D2338A mTOR mouse knock-in model and show that it is useful to study the kinase-independent function of mTOR and for assessing the off-target effects of mTOR kinase inhibitors. We found that while the mTOR KI mice in hematopoietic system displayed similar phenotypes to that of mTOR KO mice, they have significantly prolonged survival time than the KO mice. Whereas AZD2014 was mostly on-target in suppressing mTOR kinase activity, mimicking that seen in KI stem cells in transcriptome analysis, off-target genes in KI cells induced by AZD2014 including Ahnak2, Emp1, Lilrb4, Tpsb2, and Cma1 were detected. Our studies reveal kinase-independent function of mTOR in hematopoiesis and presents a mouse model for precisely assessing specificity of mTOR kinase inhibitors. Stringent test of drugs with such mouse models in the preclinical setting may provide useful information guiding the safety and efficacy of related clinical trials.
2023-08-29 | GSE235097 | GEO
Project description:Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells. It is a target of tyrosine kinase inhibitors (TKIs) used for acute myeloid leukemia treatment. Flt3 and its ligand (Flt3L) are expressed in the heart and cardiac side effects occur under Flt3-targeting TKIs. Whether Flt3/Flt3L also regulate cardiac progenitor cells (CPCs), however, is not known. The cardiac side population (SP) is a pool of heterogenous CPCs that can give rise to all cardiac lineages, hence contributing to cardiovascular homeostasis. Here we show that SP-CPCs produce and are responsive to Flt3L. Compared to wild-type, SP-CPCs from flt3L-/- mice are less abundant, with less contribution of CD45-CD34+ cells, and lower expression of gene sets related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing and compared to wild-type, flt3L-/- Sca1+CD31- SP-CPCs show increased proliferation and less vasculogenic commitment, but differentiation can be induced in the presence of receptor tyrosine kinase-activating growth factors. The observed differences are associated with decreased microvascularisation and global systolic function of flt3L-/- hearts. Thus, Flt3 contributes to a receptor tyrosine kinase signature necessary for the maintenance and functionality of SP-CPCs. These findings have potential implications regarding cardiovascular side effects observed under TKI therapy.
2021-11-30 | GSE168207 | GEO