This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, M. Y. Articles by Mischel, P. S. Search for Related Content PubMed PubMed Citation Articles by Wang, M. Y. Articles by Mischel, P. S.

Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells

Departments of ¹ Pathology and Laboratory Medicine, ² Neurology, ³ Medicine, ⁴ Molecular and Medical Pharmacology, ⁵ Henry E. Singleton Brain Tumor Program, and ⁶ Howard Hughes Medical Institute, David Geffen School of Medicine, University of California at Los Angeles; ⁷ Departments of Pediatrics, and Molecular Microbiology and Immunology, Keck School of Medicine at University of Southern California, Los Angeles, California; ⁸ Ventana Medical Systems, Tucson, Arizona; and ⁹ Ludwig Institute for Cancer Research at University of California, San Diego, California

Requests for reprints: Paul S. Mischel, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte, Los Angeles, CA 90095-1732. Phone: 310-794-5223; Fax: 310-206-8290; E-mail: pmischel{at}mednet.ucla.edu.

The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma, making it a compelling molecular target for therapy. We have recently shown that coexpression of EGFRvIII and PTEN protein by glioblastoma cells is strongly associated with clinical response to EGFR kinase inhibitor therapy. PTEN loss, by dissociating inhibition of the EGFR from downstream phosphatidylinositol 3-kinase (PI3K) pathway inhibition, seems to act as a resistance factor. Because 40% to 50% of glioblastomas are PTEN deficient, a critical challenge is to identify strategies that promote responsiveness to EGFR kinase inhibitors in patients whose tumors lack PTEN. Here, we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin enhances the sensitivity of PTEN-deficient tumor cells to the EGFR kinase inhibitor erlotinib. In two isogenic model systems (U87MG glioblastoma cells expressing EGFR, EGFRvIII, and PTEN in relevant combinations, and SF295 glioblastoma cells in which PTEN protein expression has been stably restored), we show that combined EGFR/mTOR kinase inhibition inhibits tumor cell growth and has an additive effect on inhibiting downstream PI3K pathway signaling. We also show that combination therapy provides added benefit in promoting cell death in PTEN-deficient tumor cells. These studies provide strong rationale for combined mTOR/EGFR kinase inhibitor therapy in glioblastoma patients, particularly those with PTEN-deficient tumors. (Cancer Res 2006; 66(16): 7864-9)

This article has been cited by other articles:

				P. H. Huang, A. M. Xu, and F. M. White Oncogenic EGFR Signaling Networks in Glioma Sci. Signal., September 8, 2009; 2(87): re6 - re6. [Abstract] [Full Text] [PDF]

				K. V. Lu, S. Zhu, A. Cvrljevic, T. T. Huang, S. Sarkaria, D. Ahkavan, J. Dang, E. B. Dinca, S. B. Plaisier, I. Oderberg, et al. Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients Cancer Res., September 1, 2009; 69(17): 6889 - 6898. [Abstract] [Full Text] [PDF]

				D. Guo, I. J. Hildebrandt, R. M. Prins, H. Soto, M. M. Mazzotta, J. Dang, J. Czernin, J. Y.-J. Shyy, A. D. Watson, M. Phelps, et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis PNAS, August 4, 2009; 106(31): 12932 - 12937. [Abstract] [Full Text] [PDF]

				G. Karpel-Massler, U. Schmidt, A. Unterberg, and M.-E. Halatsch Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand? Mol. Cancer Res., July 1, 2009; 7(7): 1000 - 1012. [Abstract] [Full Text] [PDF]

				G. K. Dy and A. A. Adjei Emerging Therapeutic Targets in Non-Small Cell Lung Cancer Proceedings of the ATS, April 15, 2009; 6(2): 218 - 223. [Abstract] [Full Text] [PDF]

				A. M. Puzio-Kuter, M. Castillo-Martin, C. W. Kinkade, X. Wang, T. H. Shen, T. Matos, M. M. Shen, C. Cordon-Cardo, and C. Abate-Shen Inactivation of p53 and Pten promotes invasive bladder cancer Genes & Dev., March 15, 2009; 23(6): 675 - 680. [Abstract] [Full Text] [PDF]

				S. Codeluppi, C. I. Svensson, M. P. Hefferan, F. Valencia, M. D. Silldorff, M. Oshiro, M. Marsala, and E. B. Pasquale The Rheb-mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord J. Neurosci., January 28, 2009; 29(4): 1093 - 1104. [Abstract] [Full Text] [PDF]

				Q.-W. Fan, C. Cheng, Z. A. Knight, D. Haas-Kogan, D. Stokoe, C. D. James, F. McCormick, K. M. Shokat, and W. A. Weiss EGFR Signals to mTOR Through PKC and Independently of Akt in Glioma Sci. Signal., January 27, 2009; 2(55): ra4 - ra4. [Abstract] [Full Text] [PDF]

				M. Remington, J. Chtchetinin, K. Ancheta, P. L. Nghiemphu, T. Cloughesy, and A. Lai The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity Neuro-oncol, January 1, 2009; 11(1): 22 - 32. [Abstract] [Full Text] [PDF]

				Q. Xue, B. Hopkins, C. Perruzzi, D. Udayakumar, D. Sherris, and L. E. Benjamin Palomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular Permeability Cancer Res., November 15, 2008; 68(22): 9551 - 9557. [Abstract] [Full Text] [PDF]

				S. E. Wang, B. Xiang, M. Guix, M. G. Olivares, J. Parker, C. H. Chung, A. Pandiella, and C. L. Arteaga Transforming Growth Factor {beta} Engages TACE and ErbB3 To Activate Phosphatidylinositol-3 Kinase/Akt in ErbB2-Overexpressing Breast Cancer and Desensitizes Cells to Trastuzumab Mol. Cell. Biol., September 15, 2008; 28(18): 5605 - 5620. [Abstract] [Full Text] [PDF]

				T. Trowe, S. Boukouvala, K. Calkins, R. E. Cutler Jr., R. Fong, R. Funke, S. B. Gendreau, Y. D. Kim, N. Miller, J. R. Woolfrey, et al. EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation Clin. Cancer Res., April 15, 2008; 14(8): 2465 - 2475. [Abstract] [Full Text] [PDF]

				K. Kim, J. M. Brush, P. A. Watson, N. A. Cacalano, K. S. Iwamoto, and W. H. McBride Epidermal Growth Factor Receptor vIII Expression in U87 Glioblastoma Cells Alters Their Proteasome Composition, Function, and Response to Irradiation Mol. Cancer Res., March 1, 2008; 6(3): 426 - 434. [Abstract] [Full Text] [PDF]

				D. S. Ziegler, A. L. Kung, and M. W. Kieran Anti-Apoptosis Mechanisms in Malignant Gliomas J. Clin. Oncol., January 20, 2008; 26(3): 493 - 500. [Abstract] [Full Text] [PDF]

				F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment Genes & Dev., November 1, 2007; 21(21): 2683 - 2710. [Abstract] [Full Text] [PDF]

				Q.-W. Fan, C. K. Cheng, T. P. Nicolaides, C. S. Hackett, Z. A. Knight, K. M. Shokat, and W. A. Weiss A Dual Phosphoinositide-3-Kinase {alpha}/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma Cancer Res., September 1, 2007; 67(17): 7960 - 7965. [Abstract] [Full Text] [PDF]

				A. Franovic, L. Gunaratnam, K. Smith, I. Robert, D. Patten, and S. Lee Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer PNAS, August 7, 2007; 104(32): 13092 - 13097. [Abstract] [Full Text] [PDF]

				P. H. Huang, A. Mukasa, R. Bonavia, R. A. Flynn, Z. E. Brewer, W. K. Cavenee, F. B. Furnari, and F. M. White Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma PNAS, July 31, 2007; 104(31): 12867 - 12872. [Abstract] [Full Text] [PDF]

				S. V. Bradley, E. C. Holland, G. Y. Liu, D. Thomas, T. S. Hyun, and T. S. Ross Huntingtin Interacting Protein 1 Is a Novel Brain Tumor Marker that Associates with Epidermal Growth Factor Receptor Cancer Res., April 15, 2007; 67(8): 3609 - 3615. [Abstract] [Full Text] [PDF]

				I. K. Mellinghoff, T. F. Cloughesy, and P. S. Mischel PTEN-Mediated Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors Clin. Cancer Res., January 15, 2007; 13(2): 378 - 381. [Abstract] [Full Text] [PDF]