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Ena-DATASET-RTL-03-05-2017-12:40:06:735-476 - samples

ABSTRACT: RNAseq of LC2AD with AD80 or DMSO Plenker et al., Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

OTHER RELATED OMICS DATASETS IN: PXD006006

PROVIDER: EGAD00001003316 | EGA |

REPOSITORIES: EGA

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Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.

Plenker Dennis D Riedel Maximilian M Brägelmann Johannes J Dammert Marcel A MA Chauhan Rakhee R Knowles Phillip P PP Lorenz Carina C Keul Marina M Bührmann Mike M Pagel Oliver O Tischler Verena V Scheel Andreas H AH Schütte Daniel D Song Yanrui Y Stark Justina J Mrugalla Florian F Alber Yannic Y Richters André A Engel Julian J Leenders Frauke F Heuckmann Johannes M JM Wolf Jürgen J Diebold Joachim J Pall Georg G Peifer Martin M Aerts Maarten M Gevaert Kris K Zahedi René P RP Buettner Reinhard R Shokat Kevan M KM McDonald Neil Q NQ Kast Stefan M SM Gautschi Oliver O Thomas Roman K RK Sos Martin L ML

Science translational medicine 20170601 394

Oncogenic fusion events have been identified in a broad range of tumors. Among them, <i>RET</i> rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively ...[more]

PMID: 28615362

Similar Datasets

Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.

Project description:Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.

| EGAS00001002335 | EGA

Anti-tumor activity and acquired resistance mechanism of Dovitinib (TKI258) in RET rearranged lung adenocarcinoma

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

Anti-tumor activity and acquired resistance mechanism of Dovitinib (TKI258) in RET rearranged lung adenocarcinoma

2015-09-01 | E-GEOD-69226 | biostudies-arrayexpress

Enhancer-activated RET confers protection against oxidative stress to the MLL-rearranged acute myeloid leukemia cells

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

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 2

Project description:Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression may be a novel treatment option.

2020-05-29 | PXD012971 | Pride

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 1

2020-05-29 | PXD012970 | Pride

Loss of RET promotes mesenchymal identity in neuroblastoma cells

Project description:Aberrant activation of Anaplastic Lymphoma Kinase (ALK) drives neuroblastoma (NB). Previous work has identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK driven gene signature in NB. To further address the role of RET in NB, RET knock-out (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MET RTKs as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.

2021-09-10 | PXD024551 | Pride

microRNA expression profiling in TPC1 cell line treated with the RTK inhibitor RPI-1

Project description:We treated the papillary thyroid carcinoma-derived cell line TPC1 with the RTK inhibitor RPI-1 to obtain a thyroid carcinoma cell model. The RET tyrosine kinase is a target of the inhibitor. microRNA expression changes were evaluated comparing cells treated with the inhibitor fo 24 hours versus cells treated with DMSO for 24 hours.

2014-06-30 | GSE49401 | GEO

Gene expression profiling in TPC1 cell line treated with the RTK inhibitor RPI-1

Project description:We treated the papillary thyroid carcinoma-derived cell line TPC1 with the RTK inhibitor RPI-1 to obtain a thyroid carcinoma cell model. The RET tyrosine kinase is a target of the inhibitor. Gene expression changes were evaluated comparing cells treated with the inhibitor for 24 hours versus cells treated with DMSO for 24 hours.

2014-06-30 | GSE49414 | GEO

Gene expression profiling in TPC1 cell line treated with the RTK inhibitor RPI-1

Project description:We treated the papillary thyroid carcinoma-derived cell line TPC1 with the RTK inhibitor RPI-1 to obtain a thyroid carcinoma cell model. The RET tyrosine kinase is a target of the inhibitor. Gene expression changes were evaluated comparing cells treated with the inhibitor for 24 hours versus cells treated with DMSO for 24 hours. Biological triplicates for RPI-1 and DMSO treated cells were generated by independent treatments and total RNA extractions.

2014-06-30 | E-GEOD-49414 | biostudies-arrayexpress

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