PXD030715 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Activation of STAT3 through SRC and EGFR Drives Resistance to a Mitotic Kinesin Inhibitor in Glioblastoma |
Description | The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting. |
HostingRepository | PRIDE |
AnnounceDate | 2023-05-10 |
AnnouncementXML | Submission_2023-05-10_09:04:17.005.xml |
DigitalObjectIdentifier | https://dx.doi.org/10.6019/PXD030715 |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Supported dataset by repository |
PrimarySubmitter | LaurenStopfer |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-01-04 04:07:39 | ID requested | |
⏵ 1 | 2023-05-10 09:04:17 | announced | |
2 | 2023-11-14 08:45:54 | announced | 2023-11-14: Updated project metadata. |
Publication List
10.6019/PXD030715; |
Kenchappa RS, Dovas A, Argenziano MG, Meyer CT, Stopfer LE, Banu MA, Pereira B, Griffith J, Mohammad A, Talele S, Haddock A, Zarco N, Elmquist W, White F, Quaranta V, Sims P, Canoll P, Rosenfeld SS, Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma. Cell Rep, 39(12):110991(2022) [pubmed] |
Keyword List
submitter keyword: phosphotyrosine, Glioblastoma, therapeutic resistance |
Contact List
ForestWhite |
contact affiliation | Department of Biological Engineering, MIT |
contact email | fwhite@mit.edu |
lab head | |
LaurenStopfer |
contact affiliation | MIT |
contact email | lstopfer@mit.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD030715
- Label: PRIDE project
- Name: Activation of STAT3 through SRC and EGFR Drives Resistance to a Mitotic Kinesin Inhibitor in Glioblastoma