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, R. Nagle, D. Bearss

Research output: Contribution to journalArticle

203 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
StatePublished - Jun 7 2007
Externally publishedYes

Keywords

  • GIST
  • Kit mutations
  • Morphological change
  • Tyrosine kinases

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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