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Science 318 (5848): 287-290

Copyright © 2007 by the American Association for the Advancement of Science

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*

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.

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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Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244).
J. R. Dry, S. Pavey, C. A. Pratilas, C. Harbron, S. Runswick, D. Hodgson, C. Chresta, R. McCormack, N. Byrne, M. Cockerill, et al. (2010)
Cancer Res. 70, 2264-2273
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The PI3K Pathway As Drug Target in Human Cancer.
K. D. Courtney, R. B. Corcoran, and J. A. Engelman (2010)
J. Clin. Oncol. 28, 1075-1083
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Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence.
A. Mukasa, J. Wykosky, K. L. Ligon, L. Chin, W. K. Cavenee, and F. Furnari (2010)
PNAS 107, 2616-2621
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Silencing of RON Receptor Signaling Promotes Apoptosis and Gemcitabine Sensitivity in Pancreatic Cancers.
J. Logan-Collins, R. M. Thomas, P. Yu, D. Jaquish, E. Mose, R. French, W. Stuart, R. McClaine, B. Aronow, R. M. Hoffman, et al. (2010)
Cancer Res. 70, 1130-1140
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Standard and Emerging Therapies for Metastatic Differentiated Thyroid Cancer.
C. J. O'Neill, J. Oucharek, D. Learoyd, and S. B. Sidhu (2010)
Oncologist 15, 146-156
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A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy.
J. J. Raizer, L. E. Abrey, A. B. Lassman, S. M. Chang, K. R. Lamborn, J. G. Kuhn, W.K. A. Yung, M. R. Gilbert, K. A. Aldape, P. Y. Wen, et al. (2010)
Neuro Oncology 12, 95-103
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The ATM Inhibitor KU-55933 Suppresses Cell Proliferation and Induces Apoptosis by Blocking Akt In Cancer Cells with Overactivated Akt.
Y. Li and D.-Q. Yang (2010)
Mol. Cancer Ther. 9, 113-125
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Combining Targeted Therapies: Practical Issues to Consider at the Bench and Bedside.
J. Rodon, J. Perez, and R. Kurzrock (2010)
Oncologist 15, 37-50
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Science Signaling Podcast: 15 December 2009.
P. S. Mischel and A. M. VanHook (2009)
Science Signaling 2, pc23
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EGFR Signaling Through an Akt-SREBP-1-Dependent, Rapamycin-Resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy.
D. Guo, R. M. Prins, J. Dang, D. Kuga, A. Iwanami, H. Soto, K. Y. Lin, T. T. Huang, D. Akhavan, M. B. Hock, et al. (2009)
Science Signaling 2, ra82
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Human cancers converge at the HIF-2{alpha} oncogenic axis.
A. Franovic, C. E. Holterman, J. Payette, and S. Lee (2009)
PNAS 106, 21306-21311
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PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor.
F. Perrone, L. Da Riva, M. Orsenigo, M. Losa, G. Jocolle, C. Millefanti, E. Pastore, A. Gronchi, M. A. Pierotti, and S. Pilotti (2009)
Neuro Oncology 11, 725-736
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Global Effects of Kinase Inhibitors on Signaling Networks Revealed by Quantitative Phosphoproteomics.
C. Pan, J. V. Olsen, H. Daub, and M. Mann (2009)
Mol. Cell. Proteomics 8, 2796-2808
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The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways.
M. Rahmani, A. Anderson, J. R. Habibi, T. R. Crabtree, M. Mayo, H. Harada, A. Ferreira-Gonzalez, P. Dent, and S. Grant (2009)
Blood 114, 4507-4516
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