Publication Date:
2007-09-18
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stommel, Jayne M -- Kimmelman, Alec C -- Ying, Haoqiang -- Nabioullin, Roustem -- Ponugoti, Aditya H -- Wiedemeyer, Ruprecht -- Stegh, Alexander H -- Bradner, James E -- Ligon, Keith L -- Brennan, Cameron -- Chin, Lynda -- DePinho, Ronald A -- 5P01CA95616/CA/NCI NIH HHS/ -- R01CA99041/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2007 Oct 12;318(5848):287-90. Epub 2007 Sep 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17872411" target="_blank"〉PubMed〈/a〉
Keywords:
Antineoplastic Agents/*pharmacology
;
Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use
;
Brain Neoplasms/drug therapy/*enzymology
;
Cell Line, Tumor
;
Cell Survival
;
Enzyme Activation
;
Erlotinib Hydrochloride
;
Glioblastoma/drug therapy/*enzymology
;
Humans
;
Indoles/pharmacology
;
PTEN Phosphohydrolase/genetics/metabolism
;
Phosphatidylinositol 3-Kinases/metabolism
;
Phosphorylation
;
Piperazines/pharmacology
;
Protein Kinase Inhibitors/*pharmacology
;
Proto-Oncogene Proteins/metabolism
;
Proto-Oncogene Proteins c-met
;
Quinazolines/pharmacology
;
Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism
;
Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism
;
Receptors, Growth Factor/metabolism
;
Signal Transduction
;
Sulfonamides/pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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