Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

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
Prev | Table of Contents | Next

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers.
K. Yonesaka, K. Zejnullahu, N. Lindeman, A. J. Homes, D. M. Jackman, F. Zhao, A. M. Rogers, B. E. Johnson, and P. A. Janne (2008)
Clin. Cancer Res. 14, 6963-6973
   Abstract »    Full Text »    PDF »
Illuminating signaling network functional biology through quantitative phosphoproteomic mass spectrometry.
N. C. Tedford, F. M. White, and J. A. Radding (2008)
Brief Funct Genomic Proteomic
   Abstract »    Full Text »    PDF »
Single-Agent and Combination Therapeutic Strategies to Inhibit Hepatocyte Growth Factor/MET Signaling in Cancer.
L. Toschi and P. A. Janne (2008)
Clin. Cancer Res. 14, 5941-5946
   Abstract »    Full Text »    PDF »
Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity.
H. P. Eikesdal, H. Sugimoto, G. Birrane, Y. Maeshima, V. G. Cooke, M. Kieran, and R. Kalluri (2008)
PNAS 105, 15040-15045
   Abstract »    Full Text »    PDF »
Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS.
U. Guha, R. Chaerkady, A. Marimuthu, A. S. Patterson, M. K. Kashyap, H. C. Harsha, M. Sato, J. S. Bader, A. E. Lash, J. D. Minna, et al. (2008)
PNAS 105, 14112-14117
   Abstract »    Full Text »    PDF »
Therapeutic Application of Noncytotoxic Molecular Targeted Therapy in Gliomas: Growth Factor Receptors and Angiogenesis Inhibitors.
A. Idbaih, F. Ducray, M. Sierra Del Rio, K. Hoang-Xuan, and J.-Y. Delattre (2008)
Oncologist 13, 978-992
   Abstract »    Full Text »    PDF »
Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma.
A. H. Stegh, S. Kesari, J. E. Mahoney, H. T. Jenq, K. L. Forloney, A. Protopopov, D. N. Louis, L. Chin, and R. A. DePinho (2008)
PNAS 105, 10703-10708
   Abstract »    Full Text »    PDF »
Malignant Gliomas in Adults.
P. Y. Wen and S. Kesari (2008)
N. Engl. J. Med. 359, 492-507
   Full Text »    PDF »
EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer.
J. P. Koivunen, C. Mermel, K. Zejnullahu, C. Murphy, E. Lifshits, A. J. Holmes, H. G. Choi, J. Kim, D. Chiang, R. Thomas, et al. (2008)
Clin. Cancer Res. 14, 4275-4283
   Abstract »    Full Text »    PDF »
MicroRNA miR-199a* Regulates the MET Proto-oncogene and the Downstream Extracellular Signal-regulated Kinase 2 (ERK2).
S. Kim, U. J. Lee, M. N. Kim, E.-J. Lee, J. Y. Kim, M. Y. Lee, S. Choung, Y. J. Kim, and Y.-C. Choi (2008)
J. Biol. Chem. 283, 18158-18166
   Abstract »    Full Text »    PDF »
Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors.
C. Tarn, L. Rink, E. Merkel, D. Flieder, H. Pathak, D. Koumbi, J. R. Testa, B. Eisenberg, M. von Mehren, and A. K. Godwin (2008)
PNAS 105, 8387-8392
   Abstract »    Full Text »    PDF »
Inhibition of N-Linked Glycosylation Disrupts Receptor Tyrosine Kinase Signaling in Tumor Cells.
J. N. Contessa, M. S. Bhojani, H. H. Freeze, A. Rehemtulla, and T. S. Lawrence (2008)
Cancer Res. 68, 3803-3809
   Abstract »    Full Text »    PDF »
Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas.
E. C. Brantley and E. N. Benveniste (2008)
Mol. Cancer Res. 6, 675-684
   Abstract »    Full Text »    PDF »
Integrative Approaches to Identify and Validate Kinase Oncogenes.
W. C Hahn (2008)
Am. Assoc. Cancer Res. Educ. Book 2008, 281-284
   Abstract »    Full Text »    PDF »
Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better.
T. Fojo (2008)
Oncologist 13, 277-283
   Full Text »    PDF »
Directional and quantitative phosphorylation networks.
C. Jorgensen and R. Linding (2008)
Brief Funct Genomic Proteomic
   Abstract »    Full Text »    PDF »
Signaling networks assembled by oncogenic EGFR and c-Met.
A. Guo, J. Villen, J. Kornhauser, K. A. Lee, M. P. Stokes, K. Rikova, A. Possemato, J. Nardone, G. Innocenti, R. Wetzel, et al. (2008)
PNAS 105, 692-697
   Abstract »    Full Text »    PDF »


ADVERTISEMENT
Click Me!

ADVERTISEMENT

To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)