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<MSIGDB BUILD_DATE="Jan 29, 2026" VERSION="2026.1.Hs" NAME="export">
    <GENESET STANDARD_NAME="MAHADEVAN_IMATINIB_RESISTANCE_UP" SYSTEMATIC_NAME="M18876" HISTORICAL_NAMES="" PMID="17325667" 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" GEOID="" EXACT_SOURCE="Table 1A" GENESET_LISTING_URL="" EXTERNAL_DETAILS_URL="" CHIP="HUMAN_GENE_SYMBOL" CONTRIBUTOR="Arthur Liberzon" CONTRIBUTOR_ORG="MSigDB Team" 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." TAGS="" MEMBERS="ALDH1A1,AXL,BAMBI,CD24,CRIM1,CXCL14,CYTL1,DKK3,GREM1,HSD17B2,KYNU,MYO10,NNMT,PDGFC,SCN3A,SERPINE2,SLC1A1,SPANXA1,SPANXA2,SPANXB1,SPANXB2,SPANXC,SPOCK" MEMBERS_SYMBOLIZED="ALDH1A1,AXL,BAMBI,CD24,CRIM1,CXCL14,CYTL1,DKK3,GREM1,HSD17B2,KYNU,MYO10,NNMT,PDGFC,SCN3A,SERPINE2,SLC1A1,SPANXA1,SPANXA2,SPANXB1,SPANXC,SPOCK1" MEMBERS_EZID="100133941,216,25805,26585,27122,30014,3294,4651,4837,51232,5270,54360,558,56034,6328,64663,6505,6695,728695,728712,8942,9547" MEMBERS_MAPPING="ALDH1A1,ALDH1A1,216|AXL,AXL,558|BAMBI,BAMBI,25805|CD24,CD24,100133941|CRIM1,CRIM1,51232|CXCL14,CXCL14,9547|CYTL1,CYTL1,54360|DKK3,DKK3,27122|GREM1,GREM1,26585|HSD17B2,HSD17B2,3294|KYNU,KYNU,8942|MYO10,MYO10,4651|NNMT,NNMT,4837|PDGFC,PDGFC,56034|SCN3A,SCN3A,6328|SERPINE2,SERPINE2,5270|SLC1A1,SLC1A1,6505|SPANXA1,SPANXA1,30014|SPANXA2,SPANXA2,728712|SPANXB1,SPANXB1,728695|SPANXB2,SPANXB1,728695|SPANXC,SPANXC,64663|SPOCK,SPOCK1,6695" FILTERED_BY_SIMILARITY="" FOUNDER_NAMES="" REFINEMENT_DATASETS="" VALIDATION_DATASETS="" CATEGORY_CODE="C2" ORGANISM="Homo sapiens" SUB_CATEGORY_CODE="CGP"/>
</MSIGDB>
