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Originally published in Science Express on 13 September 2007
Science 12 October 2007:
Vol. 318. no. 5848, pp. 287 - 290
DOI: 10.1126/science.1142946
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Reports

Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies

Jayne M. Stommel,1 Alec C. Kimmelman,1,2 Haoqiang Ying,1 Roustem Nabioullin,3 Aditya H. Ponugoti,3 Ruprecht Wiedemeyer,1 Alexander H. Stegh,1 James E. Bradner,4 Keith L. Ligon,1,5 Cameron Brennan,6 Lynda Chin,1,3,7 Ronald A. DePinho1,3,8*

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.

1 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
2 Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA 02115, USA.
3 Center for Applied Cancer Science, Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4 Division of Hematologic Neoplasia, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
5 Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
6 Departments of Neurosurgery, Memorial Sloan Kettering Cancer Center and Neurological Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA.
7 Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA,
8 Departments of Medicine and Genetics, Harvard Medical School, Boston, MA 02115, USA.

* To whom correspondence should be addressed. E-mail: ron_depinho{at}dfci.harvard.edu

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