Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies Journal Article
| Authors: | Stommel, J. M.; Kimmelman, A. C.; Ying, H.; Nabioullin, R.; Ponugoti, A. H.; Wiedemeyer, R.; Stegh, A. H.; Bradner, J. E.; Ligon, K. L.; Brennan, C.; Chin, L.; DePinho, R. A. |
| Article Title: | Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies |
| Abstract: | Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs. |
| Keywords: | signal transduction; unclassified drug; human cell; proto-oncogene proteins; erlotinib; drug efficacy; antineoplastic agents; brain neoplasms; cell survival; imatinib; antineoplastic combined chemotherapy protocols; rna interference; receptor, epidermal growth factor; enzyme activation; tumor xenograft; cell line, tumor; phosphorylation; protein tyrosine kinase inhibitor; protein kinase inhibitors; rna; brain; glioma cell; sulfonamides; glioblastoma; tumor cell line; 1-phosphatidylinositol 3-kinase; pten phosphohydrolase; tyrosine kinase receptor; tumor cell; piperazines; receptor protein-tyrosine kinases; tumor growth; tumor; indoles; quinazolines; downstream processing; scatter factor receptor; enzyme; receptors, growth factor; growth; hypothesis testing; su 11274 |
| Journal Title: | Science |
| Volume: | 318 |
| Issue: | 5848 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2007-10-12 |
| Start Page: | 287 |
| End Page: | 290 |
| Language: | English |
| DOI: | 10.1126/science.1142946 |
| PUBMED: | 17872411 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 273" - "Export Date: 17 November 2011" - "CODEN: SCIEA" - "Source: Scopus" |
