STANDARD_NAME MAHADEVAN_IMATINIB_RESISTANCE_UP SYSTEMATIC_NAME M18876 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/MAHADEVAN_IMATINIB_RESISTANCE_UP NAMESPACE HUMAN_GENE_SYMBOL DESCRIPTION_BRIEF Top genes up-regulated in the GIST (gastrointestinal stromal tumor) cell line resistant to imatinib [PubChem=5291] compared to the parental cell line sensitive to the drug. DESCRIPTION_FULL KIT or alpha-platelet-derived growth factor receptor (alpha-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. PMID 17325667 GEOID AUTHORS 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 CONTRIBUTOR Arthur Liberzon CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Table 1A FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS ALDH1A1,AXL,BAMBI,CD24,CRIM1,CXCL14,CYTL1,DKK3,GREM1,HSD17B2,KYNU,MYO10,NNMT,PDGFC,SCN3A,SERPINE2,SLC1A1,SPANXA1,SPANXA2,SPANXB1,SPANXB2,SPANXC,SPOCK GENE_SYMBOLS ALDH1A1,AXL,BAMBI,CD24,CRIM1,CXCL14,CYTL1,DKK3,GREM1,HSD17B2,KYNU,MYO10,NNMT,PDGFC,SCN3A,SERPINE2,SLC1A1,SPANXA1,SPANXA2,SPANXB1,SPANXB1,SPANXC,SPOCK1 FOUNDER_NAMES