<?xml version="1.0" encoding="UTF-8" standalone="yes"?>

<!-- Copyright (c) 2004-2026 Broad Institute, Inc., Massachusetts Institute of Technology, and Regents of the University of California.  All rights reserved.
     See license terms at www.gsea-msigdb.org/gsea/license_terms_list. Please note that certain gene sets have special access terms.
-->
<MSIGDB BUILD_DATE="Jan 29, 2026" VERSION="2026.1.Hs" NAME="export">
    <GENESET STANDARD_NAME="MAHADEVAN_IMATINIB_RESISTANCE_DN" SYSTEMATIC_NAME="M11367" 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 1B" GENESET_LISTING_URL="" EXTERNAL_DETAILS_URL="" CHIP="HUMAN_GENE_SYMBOL" CONTRIBUTOR="Arthur Liberzon" CONTRIBUTOR_ORG="MSigDB Team" DESCRIPTION_BRIEF="Top genes down-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="ABCG1,ALDH1A2,BCHE,CA2,CHODL,CST1,CXCL12,CXCR4,FGL2,GDF10,HAND1,KIT,LPHN2,MEOX2,MYOC,PIP5K1B,PRG1,PTGIS,TMEM16A,VCAM1" MEMBERS_SYMBOLIZED="ABCG1,ADGRL2,ALDH1A2,ANO1,BCHE,CA2,CHODL,CST1,CXCL12,CXCR4,FGL2,GDF10,HAND1,KIT,MEOX2,MYOC,PIP5K1B,PTGIS,SRGN,VCAM1" MEMBERS_EZID="10875,140578,1469,23266,2662,3815,4223,4653,55107,5552,5740,590,6387,7412,760,7852,8395,8854,9421,9619" MEMBERS_MAPPING="ABCG1,ABCG1,9619|ALDH1A2,ALDH1A2,8854|BCHE,BCHE,590|CA2,CA2,760|CHODL,CHODL,140578|CST1,CST1,1469|CXCL12,CXCL12,6387|CXCR4,CXCR4,7852|FGL2,FGL2,10875|GDF10,GDF10,2662|HAND1,HAND1,9421|KIT,KIT,3815|LPHN2,ADGRL2,23266|MEOX2,MEOX2,4223|MYOC,MYOC,4653|PIP5K1B,PIP5K1B,8395|PRG1,SRGN,5552|PTGIS,PTGIS,5740|TMEM16A,ANO1,55107|VCAM1,VCAM1,7412" FILTERED_BY_SIMILARITY="" FOUNDER_NAMES="" REFINEMENT_DATASETS="" VALIDATION_DATASETS="" CATEGORY_CODE="C2" ORGANISM="Homo sapiens" SUB_CATEGORY_CODE="CGP"/>
</MSIGDB>
