دورية أكاديمية
أعرض في EDS

A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma.

التفاصيل البيبلوغرافية
العنوان: A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma.
المؤلفون: Wykosky J; Ludwig Institute for Cancer Research, La Jolla, California., Hu J; Department of Pathology, University of California San Diego, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California., Gomez GG; Ludwig Institute for Cancer Research, La Jolla, California., Taylor T; Ludwig Institute for Cancer Research, La Jolla, California., Villa GR; Ludwig Institute for Cancer Research, La Jolla, California., Pizzo D; Department of Pathology, University of California San Diego, La Jolla, California., VandenBerg SR; Department of Pathology, University of California San Diego, La Jolla, California., Thorne AH; Ludwig Institute for Cancer Research, La Jolla, California., Chen CC; The Moores Cancer Center, University of California San Diego, La Jolla, California., Mischel PS; Ludwig Institute for Cancer Research, La Jolla, California. Department of Pathology, University of California San Diego, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California., Gonias SL; Department of Pathology, University of California San Diego, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California., Cavenee WK; Ludwig Institute for Cancer Research, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California., Furnari FB; Ludwig Institute for Cancer Research, La Jolla, California. Department of Pathology, University of California San Diego, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California. ffurnari@ucsd.edu.
المصدر: Cancer research [Cancer Res] 2015 Jan 15; Vol. 75 (2), pp. 394-404. Date of Electronic Publication: 2014 Nov 28.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]
مواضيع طبية MeSH: Apoptosis Regulatory Proteins/*metabolism , Brain Neoplasms/*metabolism , ErbB Receptors/*antagonists & inhibitors , Glioblastoma/*metabolism , Membrane Proteins/*metabolism , Proto-Oncogene Proteins/*metabolism , Receptors, Urokinase Plasminogen Activator/*metabolism, Animals ; Bcl-2-Like Protein 11 ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Cell Line, Tumor ; ErbB Receptors/genetics ; Erlotinib Hydrochloride ; Female ; Gefitinib ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Heterografts ; Humans ; Mice ; Mice, Nude ; Quinazolines/pharmacology ; Signal Transduction/drug effects
مستخلص: EGFR is the most common genetically altered oncogene in glioblastoma (GBM), but small-molecule EGFR tyrosine kinase inhibitors (TKI) have failed to yield durable clinical benefit. Here, we show that in two novel model systems of acquired resistance to EGFR TKIs, elevated expression of urokinase plasminogen activator (uPA) drives signaling through the MAPK pathway, which results in suppression of the proapoptotic BCL2-family member protein BIM (BCL2L11). In patient-derived GBM cells and genetic GBM models, uPA is shown to suppress BIM levels through ERK1/2 phosphorylation, which can be reversed by siRNA-mediated knockdown of uPA. TKI-resistant GBMs are resensitized to EGFR TKIs by pharmacologic inhibition of MEK or a BH3 mimetic drug to replace BIM function. A link between the uPA-uPAR-ERK1/2 pathway and BIM has not been previously demonstrated in GBM, and involvement of this signaling axis in resistance provides rationale for a new strategy to target EGFR TKI-resistant GBM.
(©2014 American Association for Cancer Research.)
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معلومات مُعتمدة: R01-NS080939 United States NS NINDS NIH HHS; R01 CA169096 United States CA NCI NIH HHS; F32 NS066519 United States NS NINDS NIH HHS; F32-NS066519 United States NS NINDS NIH HHS; R01 NS080939 United States NS NINDS NIH HHS; R01-CA169096 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Apoptosis Regulatory Proteins)
0 (BCL2L11 protein, human)
0 (Bcl-2-Like Protein 11)
0 (Bcl2l11 protein, mouse)
0 (Membrane Proteins)
0 (Proto-Oncogene Proteins)
0 (Quinazolines)
0 (Receptors, Urokinase Plasminogen Activator)
DA87705X9K (Erlotinib Hydrochloride)
EC 2.7.10.1 (ErbB Receptors)
S65743JHBS (Gefitinib)
تواريخ الأحداث: Date Created: 20141130 Date Completed: 20150403 Latest Revision: 20220331
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC4297573
DOI: 10.1158/0008-5472.CAN-14-2004
PMID: 25432173
قاعدة البيانات: MEDLINE
الوصف
تدمد:1538-7445
DOI:10.1158/0008-5472.CAN-14-2004