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Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2009 Jan; Vol. 8 (1), pp. 127-34. - Publication Year :
- 2009
-
Abstract
- Focal adhesion kinase (FAK) is often up-regulated in a variety of malignancies, including gastrointestinal stromal tumor (GIST), and its overexpression seems to be associated with tumor progressiveness and poor prognosis. GIST is well known to have a mutation to c-KIT; thus, a specific c-KIT inhibitor (imatinib) is recognized as the first-line chemotherapy for GIST, although a certain type of c-KIT mutation reveals a resistance to imatinib due to as yet uncertain molecular mechanisms. To assess the c-KIT mutation-related variation of cellular responses to imatinib, murine lymphocyte-derived Ba/F3 cells, which are stably transduced with different types of c-KIT mutation, were treated with either imatinib or a FAK inhibitor (TAE226), and their antitumor effects were determined in vitro and in vivo. A mutation at exon 11 (KITdel559-560) displayed a high sensitivity to imatinib, whereas that at exon 17 (KIT820Tyr) showed a significant resistance to imatinib in vitro and in vivo. KIT820Tyr cells appeared to maintain the activities of FAK and AKT under the imatinib treatment, suggesting that FAK might play a role in cell survival in imatinib-resistant cells. When FAK activity in those cells was inhibited by TAE226, cell growth was equally suppressed and the cells underwent apoptosis regardless of the c-KIT mutation types. Oral administration of TAE226 significantly diminished tumor growth in nude mice bearing KIT(820Tyr) xenografts. In summary, c-KIT mutation at exon 17 displayed a resistance to imatinib with maintained activations of FAK and subsequent survival signals. Targeting FAK could be a potential therapeutic strategy for imatinib-resistant GISTs.
- Subjects :
- Administration, Oral
Animals
Benzamides
Cell Line
Cell Proliferation drug effects
Female
Focal Adhesion Protein-Tyrosine Kinases metabolism
Gastrointestinal Stromal Tumors genetics
Gastrointestinal Stromal Tumors pathology
Imatinib Mesylate
Mice
Mice, Nude
Morpholines administration & dosage
Morpholines therapeutic use
Mutation genetics
Proto-Oncogene Proteins c-akt metabolism
Proto-Oncogene Proteins c-kit genetics
Proto-Oncogene Proteins c-kit metabolism
Substrate Specificity
Drug Resistance, Neoplasm drug effects
Focal Adhesion Protein-Tyrosine Kinases antagonists & inhibitors
Gastrointestinal Stromal Tumors drug therapy
Gastrointestinal Stromal Tumors enzymology
Piperazines therapeutic use
Pyrimidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1535-7163
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 19139121
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-08-0884