title: A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma.
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.
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, California.
authors.forename: Jill
authors.initials: J
authors.lastname: Wykosky
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, California.
authors.forename: German G
authors.initials: GG
authors.lastname: Gomez
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, California.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Taylor
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, California.
authors.forename: Genaro R
authors.initials: GR
authors.lastname: Villa
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California.
authors.forename: Donald
authors.initials: D
authors.lastname: Pizzo
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California.
authors.forename: Scott R
authors.initials: SR
authors.lastname: VandenBerg
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, California.
authors.forename: Amy Haseley
authors.initials: AH
authors.lastname: Thorne
authors.affiliation: The Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, California. The Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: 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.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D055293:Receptors, Urokinase Plasminogen Activator; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib