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

Jayne M. Stommel, Alec C. Kimmelman, Haoqiang Ying, Roustem Nabioullin, Aditya H. Ponugoti, Ruprecht Wiedemeyer, Alexander H. Stegh, James E. Bradner, Keith L. Ligon, Cameron Brennan, Lynda Chin, Ronald A. DePinho*

*Corresponding author for this work

Research output: Contribution to journalArticle

699 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)287-290
Number of pages4
JournalScience
Volume318
Issue number5848
DOIs
StatePublished - Oct 12 2007

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ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

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. (2007). Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science, 318(5848), 287-290. https://doi.org/10.1126/science.1142946