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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) signalingpathway have shown promising anticancer activity, but theirefficacy in the brain tumor glioblastoma multiforme (GBM) andother solid tumors has been modest. We hypothesized that multipleRTKs are coactivated in these tumors and that redundant inputsdrive and maintain downstream signaling, thereby limiting theefficacy of therapies targeting single RTKs. Tumor cell lines,xenotransplants, and primary tumors indeed show multiple concomitantlyactivated RTKs. Combinations of RTK inhibitors and/or RNA interference,but not single agents, decreased signaling, cell survival, andanchorage-independent growth even in glioma cells deficientin PTEN, a frequently inactivated inhibitor of PI3K. Thus, effectiveGBM therapy may require combined regimens targeting multipleRTKs.
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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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
|Abstract »|Full Text »|PDF »
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
|Abstract »|Full Text »|PDF »
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
|Abstract »|Full Text »|PDF »
Response to imatinib plus sirolimus in advanced chordoma.
S. Stacchiotti, A. Marrari, E. Tamborini, E. Palassini, E. Virdis, A. Messina, F. Crippa, C. Morosi, A. Gronchi, S. Pilotti, et al. (2009)
Ann. Onc.
20, 1886-1894
|Abstract »|Full Text »|PDF »
Phase II Study of Neoadjuvant Imatinib in Glioblastoma: Evaluation of Clinical and Molecular Effects of the Treatment.
E. Razis, P. Selviaridis, S. Labropoulos, J. L. Norris, M.-J. Zhu, D. D. Song, T. Kalebic, M. Torrens, A. Kalogera-Fountzila, G. Karkavelas, et al. (2009)
Clin. Cancer Res.
15, 6258-6266
|Abstract »|Full Text »|PDF »
Targeting Sphingosine Kinase 1 Inhibits Akt Signaling, Induces Apoptosis, and Suppresses Growth of Human Glioblastoma Cells and Xenografts.
D. Kapitonov, J. C. Allegood, C. Mitchell, N. C. Hait, J. A. Almenara, J. K. Adams, R. E. Zipkin, P. Dent, T. Kordula, S. Milstien, et al. (2009)
Cancer Res.
69, 6915-6923
|Abstract »|Full Text »|PDF »
Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma.
B. Neyns, J. Sadones, E. Joosens, F. Bouttens, L. Verbeke, J.-F. Baurain, L. D'Hondt, T. Strauven, C. Chaskis, P. In't Veld, et al. (2009)
Ann. Onc.
20, 1596-1603
|Abstract »|Full Text »|PDF »
Striking the balance between PTEN and PDK1: it all depends on the cell context.
A. Iwanami, T. F. Cloughesy, and P. S. Mischel (2009)
Genes & Dev.
23, 1699-1704
|Abstract »|Full Text »|PDF »
The Green Tea Polyphenol EGCG Potentiates the Antiproliferative Activity of c-Met and Epidermal Growth Factor Receptor Inhibitors in Non-small Cell Lung Cancer Cells.
S. A. Milligan, P. Burke, D. T. Coleman, R. L. Bigelow, J. J. Steffan, J. L. Carroll, B. J. Williams, and J. A. Cardelli (2009)
Clin. Cancer Res.
15, 4885-4894
|Abstract »|Full Text »|PDF »
Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells.
K. Kawaguchi, H. Murakami, T. Taniguchi, M. Fujii, S. Kawata, T. Fukui, Y. Kondo, H. Osada, N. Usami, K. Yokoi, et al. (2009)
Carcinogenesis
30, 1097-1105
|Abstract »|Full Text »|PDF »
Differential Response of Glioma Cells to FOXO1-Directed Therapy.
Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand?.
G. Karpel-Massler, U. Schmidt, A. Unterberg, and M.-E. Halatsch (2009)
Mol. Cancer Res.
7, 1000-1012
|Abstract »|Full Text »|PDF »
EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts.
B. Lal, C. R. Goodwin, Y. Sang, C. A. Foss, K. Cornet, S. Muzamil, M. G. Pomper, J. Kim, and J. Laterra (2009)
Mol. Cancer Ther.
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|Abstract »|Full Text »|PDF »
