PXD030715

PXD030715 is an original dataset announced via ProteomeXchange.

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	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:45:49.750.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD030715
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Lauren Stopfer
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

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.

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]

submitter keyword: phosphotyrosine, Glioblastoma, therapeutic resistance

Forest White
contact affiliation	Department of Biological Engineering, MIT
contact email	fwhite@mit.edu
lab head
Lauren Stopfer
contact affiliation	MIT
contact email	lstopfer@mit.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/05/PXD030715

PRIDE project URI

• PRIDE
  1. PXD030715
     1. Label: PRIDE project
     2. Name: Activation of STAT3 through SRC and EGFR Drives Resistance to a Mitotic Kinesin Inhibitor in Glioblastoma