Human Gene Set: MAHADEVAN_RESPONSE_TO_MP470_UP


Standard name MAHADEVAN_RESPONSE_TO_MP470_UP
Systematic name M11592
Brief description Top genes up-regulated in the GIST (gastrointestinal stromal tumor) cell line resistant to imatinib [PubChem=5291] after treatment with MP470, a protein kinase inhibitor.
Full description or abstract 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.
Collection ARCHIVED: Archived Founder gene sets that are referenced by current Hallmarks
      C2_NONE: ARCHIVED Curated
            C2_CGP: ARCHIVED Chemical and Genetic Perturbations
Source publication Pubmed 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
Exact source Table 3B
Related gene sets (show 3 additional gene sets from the source publication)

(show 19 gene sets from any of these authors)
External links
Filtered by similarity ?
Source species Homo sapiens
Contributed by Arthur Liberzon (MSigDB Team)
Source platform or
identifier namespace		 UniGene_ID
Dataset references  
Download gene set format: grp | gmt | xml | json | TSV metadata
Compute overlaps ?
Compendia expression profiles ?
Advanced query
Gene families ?
Show members (show 20 source identifiers mapped to 0 genes)
Version history 3.0: First introduced


Creative Commons Attribution 4.0 International License (CC-BY-4.0)

The contents of this gene set are protected by copyright (c) 2004-2026 Broad Institute, Inc., Massachusetts Institute of Technology, and Regents of the University of California, subject to the terms and conditions of the Creative Commons Attribution 4.0 International License.

See the full MSigDB license terms here.