This Article Full Text Full Text (PDF) 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 Shi, Y. Articles by Lichtenstein, A. Search for Related Content PubMed PubMed Citation Articles by Shi, Y. Articles by Lichtenstein, A.

Enhanced Sensitivity of Multiple Myeloma Cells Containing PTEN Mutations to CCI-779¹

Division of Hematology-Oncology, West Los Angeles VA-UCLA Medical Center and Jonsson Comprehensive Cancer Center, Los Angeles, California 90073 [Y. S., J. G., L. H., J-h. H., A. L.]; Georgetown University Medical Center, Washington, D. C. 20007 [W. L.]; and Canji, Inc., San Diego, California 92121 [R. B.]

Recent work identifies the AKT kinase as a potential mediator of tumor expansionin multiple myeloma. The finding of PTEN mutations in several myeloma cell lines suggests that loss of PTEN function may be one mechanism by which AKT activity is increased in this disease. Because PTEN-deficient myeloma cells may have up-regulated activity of the mammalian target of rapamycin (mTOR), downstream of AKT, they may be particularly sensitive to mTOR inhibition. To test this hypothesis, we challenged myeloma cell lines with CCI-779, a newly developed analogue of rapamycin and an efficient inhibitor of mTOR. Three of four PTEN-deficient cell lines with constitutively active AKT were remarkably sensitive to cytoreduction and G₁ arrest induced by CCI-779 with ID₅₀ concentrations of <1 nM. In contrast, myeloma cells expressing wild-type PTEN were >1000-fold more resistant. Acute expression of a constitutively active AKT gene in CCI-779-resistant myeloma cells containing wild-type PTEN and quiescent AKT did not convert them to the CCI-779-sensitive phenotype. Conversely, expression of wild-type PTEN in CCI-779-sensitive, PTEN-deficient myeloma cells did not induce resistance. Differential sensitivity did not appear to be due to differences in the ability of CCI-779 to inhibit mTOR and induce dephosphorylation of p70S6kinase or 4E-BP1. However, CCI-779 inhibited expression of c-myc in CCI-sensitive PTEN-null myeloma cells but had no effect on expression in CCI-resistant cells. In contrast, cyclin D1 expression was not altered in either sensitive or resistant cells. These results indicate that PTEN-deficient myeloma cells are remarkably sensitive to mTOR inhibition. Although the results of transfection studies suggest that the level of PTEN and AKT function per se does not regulate sensitivity, PTEN/AKT status may be a good predictive marker of sensitivity.

This article has been cited by other articles:

				D. Liu, P. Hou, Z. Liu, G. Wu, and M. Xing Genetic Alterations in the Phosphoinositide 3-Kinase/Akt Signaling Pathway Confer Sensitivity of Thyroid Cancer Cells to Therapeutic Targeting of Akt and Mammalian Target of Rapamycin Cancer Res., September 15, 2009; 69(18): 7311 - 7319. [Abstract] [Full Text] [PDF]

				A. S. Fung, L. Wu, and I. F. Tannock Concurrent and Sequential Administration of Chemotherapy and the Mammalian Target of Rapamycin Inhibitor Temsirolimus in Human Cancer Cells and Xenografts Clin. Cancer Res., September 1, 2009; 15(17): 5389 - 5395. [Abstract] [Full Text] [PDF]

				F. Meric-Bernstam and A. M. Gonzalez-Angulo Targeting the mTOR Signaling Network for Cancer Therapy J. Clin. Oncol., May 1, 2009; 27(13): 2278 - 2287. [Abstract] [Full Text] [PDF]

				S. Han, C. Polizzano, G. P. Nielsen, F. J. Hornicek, A. E. Rosenberg, and V. Ramesh Aberrant Hyperactivation of Akt and Mammalian Target of Rapamycin Complex 1 Signaling in Sporadic Chordomas Clin. Cancer Res., March 15, 2009; 15(6): 1940 - 1946. [Abstract] [Full Text] [PDF]

				P. Frost, Y. Shi, B. Hoang, J. Gera, and A. Lichtenstein Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin Mol. Cancer Ther., January 1, 2009; 8(1): 83 - 93. [Abstract] [Full Text] [PDF]

				L. Yang, M. J. Clarke, B. L. Carlson, A. C. Mladek, M. A. Schroeder, P. Decker, W. Wu, G. J. Kitange, P. T. Grogan, J. M. Goble, et al. PTEN Loss Does Not Predict for Response to RAD001 (Everolimus) in a Glioblastoma Orthotopic Xenograft Test Panel Clin. Cancer Res., June 15, 2008; 14(12): 3993 - 4001. [Abstract] [Full Text] [PDF]

				J. A. Garcia and D. Danielpour Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies Mol. Cancer Ther., June 1, 2008; 7(6): 1347 - 1354. [Abstract] [Full Text] [PDF]

				R. J. Motzer, G. R. Hudes, B. D. Curti, D. F. McDermott, B. J. Escudier, S. Negrier, B. Duclos, L. Moore, T. O'Toole, J. P. Boni, et al. Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma J. Clin. Oncol., September 1, 2007; 25(25): 3958 - 3964. [Abstract] [Full Text] [PDF]

				H. Younes, X. Leleu, E. Hatjiharissi, A.-S. Moreau, T. Hideshima, P. Richardson, K. C. Anderson, and I. M. Ghobrial Targeting the Phosphatidylinositol 3-Kinase Pathway in Multiple Myeloma Clin. Cancer Res., July 1, 2007; 13(13): 3771 - 3775. [Abstract] [Full Text] [PDF]

				A. Gutierrez-Dalmau and J. M. Campistol The role of proliferation signal inhibitors in post-transplant malignancies Nephrol. Dial. Transplant., May 1, 2007; 22(suppl_1): i11 - i16. [Abstract] [Full Text] [PDF]

				C. Xie, R. Patel, T. Wu, J. Zhu, T. Henry, M. Bhaskarabhatla, R. Samudrala, K. Tus, Y. Gong, H. Zhou, et al. PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr Int. Immunol., April 1, 2007; 19(4): 509 - 522. [Abstract] [Full Text] [PDF]

				M. M. Stanford, J. W. Barrett, S. H. Nazarian, S. Werden, and G. McFadden Oncolytic Virotherapy Synergism with Signaling Inhibitors: Rapamycin Increases Myxoma Virus Tropism for Human Tumor Cells J. Virol., February 1, 2007; 81(3): 1251 - 1260. [Abstract] [Full Text] [PDF]

				D. Cho, S. Signoretti, M. Regan, J. W. Mier, and M. B. Atkins The Role of Mammalian Target of Rapamycin Inhibitors in the Treatment of Advanced Renal Cancer Clin. Cancer Res., January 15, 2007; 13(2): 758s - 763s. [Abstract] [Full Text] [PDF]

				L. K. Francis, Y. Alsayed, X. Leleu, X. Jia, U. K. Singha, J. Anderson, M. Timm, H. Ngo, G. Lu, A. Huston, et al. Combination Mammalian Target of Rapamycin Inhibitor Rapamycin and HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Has Synergistic Activity in Multiple Myeloma. Clin. Cancer Res., November 15, 2006; 12(22): 6826 - 6835. [Abstract] [Full Text] [PDF]

				H. Wang, H. Han, and D. D. Von Hoff Identification of an Agent Selectively Targeting DPC4 (Deleted in Pancreatic Cancer Locus 4)-Deficient Pancreatic Cancer Cells Cancer Res., October 1, 2006; 66(19): 9722 - 9730. [Abstract] [Full Text] [PDF]

				M. Hidalgo, J. C. Buckner, C. Erlichman, M. S. Pollack, J. P. Boni, G. Dukart, B. Marshall, L. Speicher, L. Moore, and E. K. Rowinsky A Phase I and Pharmacokinetic Study of Temsirolimus (CCI-779) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients with Advanced Cancer. Clin. Cancer Res., October 1, 2006; 12(19): 5755 - 5763. [Abstract] [Full Text] [PDF]

				H.-G. Wendel, A. Malina, Z. Zhao, L. Zender, S. C. Kogan, C. Cordon-Cardo, J. Pelletier, and S. W. Lowe Determinants of Sensitivity and Resistance to Rapamycin-Chemotherapy Drug Combinations In vivo. Cancer Res., August 1, 2006; 66(15): 7639 - 7646. [Abstract] [Full Text] [PDF]

				J. Bertram, J. W. Peacock, C. Tan, A. L-F. Mui, S. W. Chung, M. E. Gleave, S. Dedhar, M. E. Cox, and C. J. Ong Inhibition of the Phosphatidylinositol 3'-Kinase Pathway Promotes Autocrine Fas-Induced Death of Phosphatase and Tensin Homologue-Deficient Prostate Cancer Cells. Cancer Res., May 1, 2006; 66(9): 4781 - 4788. [Abstract] [Full Text] [PDF]

				H. Yan, P. Frost, Y. Shi, B. Hoang, S. Sharma, M. Fisher, J. Gera, and A. Lichtenstein Mechanism by Which Mammalian Target of Rapamycin Inhibitors Sensitize Multiple Myeloma Cells to Dexamethasone-Induced Apoptosis Cancer Res., February 15, 2006; 66(4): 2305 - 2313. [Abstract] [Full Text] [PDF]

				Y. Shi, H. Yan, P. Frost, J. Gera, and A. Lichtenstein Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade Mol. Cancer Ther., October 1, 2005; 4(10): 1533 - 1540. [Abstract] [Full Text] [PDF]

				J. An and M. B. Rettig Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity Mol. Cell. Biol., September 1, 2005; 25(17): 7546 - 7556. [Abstract] [Full Text] [PDF]

				S.-Y. Sun, L. M. Rosenberg, X. Wang, Z. Zhou, P. Yue, H. Fu, and F. R. Khuri Activation of Akt and eIF4E Survival Pathways by Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition Cancer Res., August 15, 2005; 65(16): 7052 - 7058. [Abstract] [Full Text] [PDF]

				W. W. Chen, D. C. Chan, C. Donald, M. B. Lilly, and A. S. Kraft Pim Family Kinases Enhance Tumor Growth of Prostate Cancer Cells Mol. Cancer Res., August 1, 2005; 3(8): 443 - 451. [Abstract] [Full Text] [PDF]

				L. Wu, D. C. Birle, and I. F. Tannock Effects of the Mammalian Target of Rapamycin Inhibitor CCI-779 Used Alone or with Chemotherapy on Human Prostate Cancer Cells and Xenografts Cancer Res., April 1, 2005; 65(7): 2825 - 2831. [Abstract] [Full Text] [PDF]

				S. Vignot, S. Faivre, D. Aguirre, and E. Raymond mTOR-targeted therapy of cancer with rapamycin derivatives Ann. Onc., April 1, 2005; 16(4): 525 - 537. [Abstract] [Full Text] [PDF]

				C. Recher, O. Beyne-Rauzy, C. Demur, G. Chicanne, C. Dos Santos, V. M.-D. Mas, D. Benzaquen, G. Laurent, F. Huguet, and B. Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF]

				J. Dong, J. Peng, H. Zhang, W. H. Mondesire, W. Jian, G. B. Mills, M.-C. Hung, and F. Meric-Bernstam Role of Glycogen Synthase Kinase 3{beta} in Rapamycin-Mediated Cell Cycle Regulation and Chemosensitivity Cancer Res., March 1, 2005; 65(5): 1961 - 1972. [Abstract] [Full Text] [PDF]

				H. Jernberg-Wiklund and K. Nilsson Toward a rational combinaTORial therapy for multiple myeloma Blood, December 15, 2004; 104(13): 3845 - 3846. [Full Text] [PDF]

				P. Frost, F. Moatamed, B. Hoang, Y. Shi, J. Gera, H. Yan, P. Frost, J. Gibbons, and A. Lichtenstein In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model Blood, December 15, 2004; 104(13): 4181 - 4187. [Abstract] [Full Text] [PDF]

				N. Raje, S. Kumar, T. Hideshima, K. Ishitsuka, D. Chauhan, C. Mitsiades, K. Podar, S. Le Gouill, P. Richardson, N. C. Munshi, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma Blood, December 15, 2004; 104(13): 4188 - 4193. [Abstract] [Full Text] [PDF]

				J. H. Reiling and E. Hafen The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila Genes & Dev., December 1, 2004; 18(23): 2879 - 2892. [Abstract] [Full Text] [PDF]

				X. Zhou, M. Tan, V. Stone Hawthorne, K. S. Klos, K.-H. Lan, Y. Yang, W. Yang, T. L. Smith, D. Shi, and D. Yu Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast Cancers Clin. Cancer Res., October 15, 2004; 10(20): 6779 - 6788. [Abstract] [Full Text] [PDF]

				J. P. Dutcher Mammalian Target of Rapamycin Inhibition Clin. Cancer Res., September 15, 2004; 10(18): 6382S - 6387S. [Abstract] [Full Text] [PDF]

				M. Hidalgo New Target, New Drug, Old Paradigm J. Clin. Oncol., June 15, 2004; 22(12): 2270 - 2272. [Full Text] [PDF]

				E. Raymond, J. Alexandre, S. Faivre, K. Vera, E. Materman, J. Boni, C. Leister, J. Korth-Bradley, A. Hanauske, and J.-P. Armand Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer J. Clin. Oncol., June 15, 2004; 22(12): 2336 - 2347. [Abstract] [Full Text] [PDF]

				T. Stromberg, A. Dimberg, A. Hammarberg, K. Carlson, A. Osterborg, K. Nilsson, and H. Jernberg-Wiklund Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone Blood, April 15, 2004; 103(8): 3138 - 3147. [Abstract] [Full Text] [PDF]

				W.-C. Noh, W. H. Mondesire, J. Peng, W. Jian, H. Zhang, J. Dong, G. B. Mills, M.-C. Hung, and F. Meric-Bernstam Determinants of Rapamycin Sensitivity in Breast Cancer Cells Clin. Cancer Res., February 1, 2004; 10(3): 1013 - 1023. [Abstract] [Full Text] [PDF]

				A. Boulay, S. Zumstein-Mecker, C. Stephan, I. Beuvink, F. Zilbermann, R. Haller, S. Tobler, C. Heusser, T. O'Reilly, B. Stolz, et al. Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells Cancer Res., January 1, 2004; 64(1): 252 - 261. [Abstract] [Full Text] [PDF]

				C. L. Sawyers Opportunities and challenges in the development of kinase inhibitor therapy for cancer Genes & Dev., December 15, 2003; 17(24): 2998 - 3010. [Full Text] [PDF]

				C. Zhou, P. A. Gehrig, Y. E. Whang, and J. F. Boggess Rapamycin Inhibits Telomerase Activity by Decreasing the hTERT mRNA Level in Endometrial Cancer Cells Mol. Cancer Ther., August 1, 2003; 2(8): 789 - 795. [Abstract] [Full Text] [PDF]