Crosstalk between KIT and FGFR3 promotes gastrointestinal stromal tumor cell growth and drug resistance

Nathalie Javidi-Sharifi, Elie Traer, Jacqueline Martinez, Anu Gupta, Takehiro Taguchi, Jennifer Dunlap, Michael C. Heinrich, Christopher L. Corless, Brian P. Rubin, Brian J. Druker, Jeffrey W. Tyner

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinibresistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinibresistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinibresistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinibnaïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib.

Original languageEnglish (US)
Pages (from-to)880-891
Number of pages12
JournalCancer Research
Volume75
Issue number5
DOIs
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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