1. ¹Arizona Cancer Center, Tucson, AZ, USA
2. ²Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
3. ³Supergen Pharmaceuticals, Salt Lake City, UT, USA

Correspondence: Dr D Mahadevan, Arizona Cancer Center, 1515 N Campbell Avenue, PO Box 245024, Tucson, AZ 85724, USA. E-mail: dmahadevan@azcc.arizona.edu

Received 23 February 2006; Revised 27 July 2006; Accepted 27 September 2006; Published online 26 February 2007.

Abstract

KIT or -platelet-derived growth factor receptor (-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.