STANDARD_NAME	MAHADEVAN_IMATINIB_RESISTANCE_DN
SYSTEMATIC_NAME	M11367
COLLECTION	C2:CGP
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/MAHADEVAN_IMATINIB_RESISTANCE_DN
NAMESPACE	HUMAN_GENE_SYMBOL
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.
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 1B
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	
SOURCE_MEMBERS	ABCG1,ALDH1A2,BCHE,CA2,CHODL,CST1,CXCL12,CXCR4,FGL2,GDF10,HAND1,KIT,LPHN2,MEOX2,MYOC,PIP5K1B,PRG1,PTGIS,TMEM16A,VCAM1
GENE_SYMBOLS	ABCG1,ALDH1A2,BCHE,CA2,CHODL,CST1,CXCL12,CXCR4,FGL2,GDF10,HAND1,KIT,ADGRL2,MEOX2,MYOC,PIP5K1B,SRGN,PTGIS,ANO1,VCAM1
FOUNDER_NAMES