FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors

Cancer Discov. 2015 Apr;5(4):438-51. doi: 10.1158/2159-8290.CD-14-0763. Epub 2015 Feb 11.

Abstract

Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GIST). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines and improved efficacy in patient-derived GIST xenografts. In addition, inhibition of MAPK signaling by imatinib was not sustained in GIST cells. An ERK rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregulation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells.

Significance: We here show that FGFR-mediated reactivation of the MAPK pathway attenuates the antiproliferation effects of imatinib in GISTs. The imatinib-induced ERK rebound can be repressed by the FGFR inhibitor BGJ398, and combined KIT and FGFR inhibition leads to increased efficacy in vitro and in patient-derived xenografts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Fibroblast Growth Factors / pharmacology
  • Gastrointestinal Stromal Tumors / drug therapy
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / metabolism*
  • Gastrointestinal Stromal Tumors / pathology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imatinib Mesylate / pharmacology*
  • Ligands
  • MAP Kinase Signaling System / drug effects*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Proteome
  • Proteomics
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Ligands
  • Protein Kinase Inhibitors
  • Proteome
  • Fibroblast Growth Factors
  • Imatinib Mesylate
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases