Glioblastoma Cell Resistance to EGFR and MET Inhibition Can Be Overcome via Blockade of FGFR-SPRY2 Bypass Signaling

Cell Rep. 2020 Mar 10;30(10):3383-3396.e7. doi: 10.1016/j.celrep.2020.02.014.


SPRY2 is a purported tumor suppressor in certain cancers that promotes tumor growth and resistance to receptor tyrosine kinase inhibitors in glioblastoma. Here, we identify a SPRY2-dependent bypass signaling mechanism in glioblastoma that drives resistance to EGFR and MET inhibition. In glioblastoma cells treated with EGFR and MET inhibitors, SPRY2 expression is initially suppressed but eventually rebounds due to NF-κB pathway activation, resultant autocrine FGFR activation, and reactivation of ERK, which controls SPRY2 transcription. In cells where FGFR autocrine signaling does not occur and ERK does not reactivate, or in which ERK reactivates but SPRY2 cannot be expressed, EGFR and MET inhibitors are more effective at promoting death. The same mechanism also drives acquired resistance to EGFR and MET inhibition. Furthermore, tumor xenografts expressing an ERK-dependent bioluminescent reporter engineered for these studies reveal that this bypass resistance mechanism plays out in vivo but can be overcome through simultaneous FGFR inhibition.

Keywords: FRA1; NF-κB; bypass resistance; combination therapy; extracellular signal-regulated kinase (ERK); glioma stem cells; heterogeneity; kinase inhibitors; nuclear factor k-light-chain-enhancer of activated B cells; small-animal imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Reporter
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Ligands
  • Membrane Proteins / metabolism*
  • Mice, Nude
  • Models, Biological
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Signal Transduction* / drug effects
  • Up-Regulation / drug effects


  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Receptors, Fibroblast Growth Factor
  • SPRY2 protein, human
  • Fibroblast Growth Factors
  • EGFR protein, human
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases