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.
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Acknowledgements
This work was supported by a Grant from the American Cancer Society (IRG7400128, CA23074). The parental GIST882 cell line was provided by Dr Jonathan Fletcher (Dana-Farber Cancer Institute, Boston). We thank Dr G Watts for help and guidance in the analysis of the gene expression profiling studies. Immunohistochemical data was generated by the TACMASS Core (Tissue Acquisition and Cellular/Molecular Analysis Shared Service) at the Arizona Cancer Center, supported by NIH Grant CA23074.
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Mahadevan, D., Cooke, L., Riley, C. et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 26, 3909–3919 (2007). https://doi.org/10.1038/sj.onc.1210173
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DOI: https://doi.org/10.1038/sj.onc.1210173
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