Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies

JM Stommel, AC Kimmelman, H Ying, R Nabioullin… - Science, 2007 - science.org
JM Stommel, AC Kimmelman, H Ying, R Nabioullin, AH Ponugoti, R Wiedemeyer, AH Stegh
Science, 2007science.org
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 …
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.
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