Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy.
PURPOSE: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. EXPERIMENTAL DESIGN: Activat...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2013
|
| _version_ | 1826266567483064320 |
|---|---|
| author | Zhang, Y van Oosterwijk, J Sicinska, E Moss, S Remillard, S van Wezel, T Bühnemann, C Hassan, A Demetri, G Bovée, J Wagner, A |
| author_facet | Zhang, Y van Oosterwijk, J Sicinska, E Moss, S Remillard, S van Wezel, T Bühnemann, C Hassan, A Demetri, G Bovée, J Wagner, A |
| author_sort | Zhang, Y |
| collection | OXFORD |
| description | PURPOSE: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. EXPERIMENTAL DESIGN: Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. RESULTS: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. CONCLUSIONS: RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors. |
| first_indexed | 2024-03-06T20:40:55Z |
| format | Journal article |
| id | oxford-uuid:344077bb-7e84-4f8f-a4a2-a013347ee8bb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:40:55Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:344077bb-7e84-4f8f-a4a2-a013347ee8bb2022-03-26T13:24:53ZFunctional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:344077bb-7e84-4f8f-a4a2-a013347ee8bbEnglishSymplectic Elements at Oxford2013Zhang, Yvan Oosterwijk, JSicinska, EMoss, SRemillard, Svan Wezel, TBühnemann, CHassan, ADemetri, GBovée, JWagner, APURPOSE: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. EXPERIMENTAL DESIGN: Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. RESULTS: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. CONCLUSIONS: RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors. |
| spellingShingle | Zhang, Y van Oosterwijk, J Sicinska, E Moss, S Remillard, S van Wezel, T Bühnemann, C Hassan, A Demetri, G Bovée, J Wagner, A Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. |
| title | Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. |
| title_full | Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. |
| title_fullStr | Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. |
| title_full_unstemmed | Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. |
| title_short | Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. |
| title_sort | functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy |
| work_keys_str_mv | AT zhangy functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT vanoosterwijkj functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT sicinskae functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT mosss functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT remillards functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT vanwezelt functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT buhnemannc functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT hassana functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT demetrig functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT boveej functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy AT wagnera functionalprofilingofreceptortyrosinekinasesanddownstreamsignalinginhumanchondrosarcomasidentifiespathwaysforrationaltargetedtherapy |