Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor Journal Article
| Authors: | Rossi, F.; Ehlers, I.; Agosti, V.; Socci, N. D.; Viale, A.; Sommer, G.; Yozgat, Y.; Manova, K.; Antonescu, C. R.; Besmer, P. |
| Article Title: | Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor |
| Abstract: | Kit receptor-activating mutations are critical in the pathogenesis of gastrointestinal stromal tumors (GIST). We investigated mechanisms of oncogenic Kit signaling and the consequences of therapeutic intervention in a mouse model of human GIST. Treatment of GIST mice with imatinib decreased cell proliferation and increased apoptosis in the tumor. Analysis of tumor tissue from imatinib-treated mice showed diminished phosphatidylinositol 3-kinase (PI3-kinase) and mammalian target of rapamycin (mTOR) signaling suggesting that oncogenic Kit signaling critically contributes to the translational response in GIST. Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST. Analysis of RNA expression profiles in GIST lesions with and without imatinib treatment showed changes in expression of IFN-inducible genes and cell cycle regulators. These results convincingly show that KitV558Δ/+ mice represent a unique faithful mouse model of human familial GIST, and they demonstrate the utility of these mice for preclinical investigations and to elucidate oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention. © 2006 by The National Academy of Sciences of the USA. |
| Keywords: | signal transduction; controlled study; pathogenesis; drug potentiation; nonhuman; cell proliferation; mouse; mammalia; animals; mice; animal tissue; gastrointestinal stromal tumor; imatinib; stem cell factor; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; apoptosis; gene expression profiling; protein kinases; animal experiment; animal model; down-regulation; pyrimidines; phosphorylation; phosphatidylinositol 3 kinase; mice, inbred c57bl; mice, transgenic; rna; oncogene; gene expression regulation, neoplastic; mammalian target of rapamycin; piperazines; disease models, animal; mammalian target of rapamycin inhibitor; cell cycle regulation; everolimus; sirolimus; kit receptor tyrosine kinase |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 103 |
| Issue: | 34 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2006-08-22 |
| Start Page: | 12843 |
| End Page: | 12848 |
| Language: | English |
| DOI: | 10.1073/pnas.0511076103 |
| PUBMED: | 16908864 |
| PROVIDER: | scopus |
| PMCID: | PMC1568935 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 52" - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work