Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Plenker D

PROVIDER: S-EPMC5805089 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

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

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Project description:DNA methylation is a mechanism of epigenetic gene regulation and genome defense conserved in many eukaryotic organisms. In Arabidopsis, the DNA methyltransferase DRM2 controls RNA-directed DNA methylation in a pathway that also involves the plant specific RNA Polymerase V (Pol V). The Arabidopsis genome also encodes an evolutionarily conserved but catalytically inactive DNA methyltransferase DRM3. Here, we show that DRM3 has moderate effects on global RNA-directed DNA methylation and small RNA abundance throughout the genome, and DRM3 protein physically interacts with Pol V. In drm3 mutants, we observe a lower level of Pol V-dependent transcripts, even though Pol V chromatin occupancy is increased at many sites in the genome. These findings suggest that DRM3 acts to promote Pol V transcriptional elongation or assist in the stabilization of Pol V transcripts, and shed further light on the mechanism of RNA-directed DNA methylation. For wildtype plants as well as drm3, drm2, and nrpe1 mutants ChIP-seq was carried out using an endogenous NRPE1 antibody given to us by the Craig Pikaard lab. Two biological replicates of ChIP-seq were also carried out using anti-Flag resin on wildtype and drm3 plants carrying a Flag epitope tagged version of NRPE1. Small RNA sequencing was carried out on Col, drm3, drm2, and nrpe1 plants. Finally, whole-genome bisulfite sequencing analysis was carried out on previously published datasets (as detailed below) which were realigned using a newer genome version and mapping protocol. As such the updated processed files are part of this submission. Please note that the drm2, drm3, and nrpe1 mutant libraries used in this study were previously published (GSE39901), as were the 2 other Col replicates used (GSE36129) as below and thus duplicated sample records were created for the convenient retrieval of the complete raw data from SRA; Bisulfite_seq-Col_1 - GSM881756 Bisulfite_seq-Col_2 - GSM1193638 Bisulfite_seq-drm3 - GSM981017 Bisulfite_seq-drm2 - GSM981015 Bisulfite_seq-nrpe1- GSM981040

Dataset Information

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

Publications

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

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