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

Jill Wykosky, Jingjing Hu, German G. Gomez, Tiffany Taylor, Genaro R. Villa, Donald Pizzo, Scott R. Van Den Berg, Amy Haseley Thorne, Clark C. Chen, Paul S. Mischel, Steven L. Gonias, Webster K. Cavenee, Frank B. Furnari

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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 patientderived 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. TKIresistant 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.

Original languageEnglish (US)
Pages (from-to)394-404
Number of pages11
JournalCancer Research
Volume75
Issue number2
DOIs
StatePublished - Jan 15 2015

Bibliographical note

Publisher Copyright:
© 2014 American Association for Cancer Research.

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