Format

Send to

Choose Destination
Cancer Res. 2015 Jan 15;75(2):394-404. doi: 10.1158/0008-5472.CAN-14-2004. Epub 2014 Nov 28.

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

Author information

1
Ludwig Institute for Cancer Research, La Jolla, California.
2
Department of Pathology, University of California San Diego, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California.
3
Department of Pathology, University of California San Diego, La Jolla, California.
4
The Moores Cancer Center, University of California San Diego, La Jolla, California.
5
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.
6
Ludwig Institute for Cancer Research, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California.
7
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.

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 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.

PMID:
25432173
PMCID:
PMC4297573
DOI:
10.1158/0008-5472.CAN-14-2004
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center