Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Brain Neoplasms
  • Glioblastoma
  • Protein Kinase Inhibitors
  • Receptor Protein-Tyrosine Kinases

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.

publication date

  • October 12, 2007

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1126/science.1142946

PubMed ID

  • 17872411

Additional Document Info

start page

  • 287

end page

  • 90

volume

  • 318

number

  • 5848