Top genes up-regulated in the GIST (gastrointestinal stromal tumor) cell line sensitive to imatinib [PubChem=5291] after treatment with MP470, a protein kinase inhibitor.
| PAG Title | Top genes up-regulated in the GIST (gastrointestinal stromal tumor) cell line sensitive to imatinib [PubChem=5291] after treatment with MP470, a protein kinase inhibitor. |
| PAG ID | MAX001721 |
| Type | A |
| Source Link |  MSigDB |
| Publication Reference | NA |
| PAG Description | 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. |
| Species | Homo sapiens |
| Quality Metric Scores | nCoCo Score: 247 |
| Information Content | Rich |
| Other IDs | M19131 |
| Base PAG ID | MAX001721 |
| Human Phenotyte Annotation | |
| Curator | PAGER curation team |
| Curator Contact | PAGER-contact@googlegroups.com |
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