A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

D. Mahadevan, L. Cooke, C. Riley, R. Swart, B. Simons, K. Della Croce, L. Wisner, M. Iorio, K. Shakalya, H. Garewal, Raymond B Nagle, D. Bearss

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196 Scopus citations

Abstract

KIT or α-platelet-derived growth factor receptor (α-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

Original languageEnglish (US)
Pages (from-to)3909-3919
Number of pages11
JournalOncogene
Volume26
Issue number27
DOIs
Publication statusPublished - Jun 7 2007

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Keywords

  • GIST
  • Kit mutations
  • Morphological change
  • Tyrosine kinases

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Mahadevan, D., Cooke, L., Riley, C., Swart, R., Simons, B., Della Croce, K., ... Bearss, D. (2007). A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene, 26(27), 3909-3919. https://doi.org/10.1038/sj.onc.1210173