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mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt

¹ Memorial Sloan-Kettering Cancer Center New York, New York; ² Vall d'Hebron University Hospital, Barcelona, Spain; ³ The University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁴ Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and ⁵ ImClone Systems Incorporated, New York, New York

Requests for reprints: Neal Rosen, Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, Box 271, 1275 York Avenue, New York, NY 10021. Phone: 212-639-2369; Fax: 212-717-3627; E-mail: rosenn{at}mskcc.org.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity. (Cancer Res 2006; 66(3): 1500-8)

	Introduction

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Activation of phosphoinositide-3-kinase (PI3K)/Akt/mTOR signaling through mutation of pathway components as well as through activation of upstream signaling molecules occurs in a majority of cancers contributing to deregulation of proliferation, resistance to apoptosis, and changes in metabolism characteristic of transformed cells (1, 2). This pathway is normally regulated by upstream receptor tyrosine kinases, especially the insulin and insulin-like growth factor I (IGF-I) receptors (IGF-IR; ref. 3). Physiologic activation of these receptors also results in feedback down-regulation of the pathway, mediated in part by mTOR/S6K-dependent loss of insulin receptor substrate-1 (IRS-1) expression (4–8). IRS-1 is the major substrate of the IGF-I and insulin receptors, responsible for the propagation of the signal induced by ligand binding (2, 9). We speculated that constitutive activation of the Akt/mTOR pathway in cancer cells would induce upstream feedback inhibition of signaling via IGF-I/insulin and perhaps other transmembrane receptors. Feedback inhibition could have marked biological and therapeutic implications. First, feedback inhibition of upstream signaling pathways could cause hypersensitivity to mTOR inhibitors and inhibition of other elements of the activated signaling pathway (so-called "oncogene addiction"; refs. 10, 11). Second, inhibition of mTOR could cause the release of feedback inhibition, paradoxically activating IGF-I signaling and reducing the antitumor effects of mTOR inhibitors. We show herein that inhibition of mTOR in cancer cell lines and in patient tumors causes activation of Akt kinase which is associated with induction of IRS-1 and is prevented by IGF-IR inhibition. Furthermore, we show that IGF-I antagonizes the antiproliferative effects of rapamycin in serum-free medium and IGF-IR inhibitors sensitize cancer cell lines to rapamycin's antiproliferative effects.

	Materials and Methods

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Cell lines, antibodies, and reagents. DU-145, MCF-7, and MDA-MB-468 were purchased from the American Type Culture Collection (Manassas, VA). Anti-IRS-1, anti-IRS-2, and anti-FKHRL1 antibodies were from Upstate Biotechnology (Waltham, MA). pAkt(S473), p-p70/S6K (T389), p70/S6K, p-GSK3/ß, GSK3, GSK3ß, Akt, Akt1, Akt 2, Akt 3, p-FKHR(S256)/p-AFX(S193), FKHR, AFX, and p-FKHR(T24)/p-FKHRL1(T32) antibodies were from Cell Signaling Technology (Beverly, MA). Rapamycin and LY294002 were from Calbiochem (San Diego, CA). NVP-AEW541 was a gift from Novartis Pharma AG (Basel, Switzerland) and A12 was a gift from ImClone Systems, Incorporated (New York, NY).

Western blotting. MDA-MB-468, DU-145, and MCF-7 cells were harvested and lysed in mRIPA or NP40 lysis buffer. Protein concentrations were determined with the bicinchoninic acid method (Pierce, Rockford, IL). Samples were subjected to SDS-PAGE. Proteins were detected using the enhanced chemiluminescence kit (Amersham Biosciences, Piscataway, NJ) and bands quantitated with Science Lab 2003 Image Gauge (Fujifilm, Tokyo, Japan).

In vitro Akt kinase assay. Cells were treated with either 1 nmol/L rapamycin for 1 or 4 hours, DMSO vehicle (time 0), 10 µmol/L LY294002 pretreatment for 1 hour followed by 1 or 4 hours of 1 nmol/L rapamycin exposure, 800 nmol/L NVP-AEW541 pretreatment for 1 hour followed by 1 or 4 hours of 1 nmol/L rapamycin, or 10 nmol/L A12 pretreatment for 1 hour followed by 4 hours of 1 nmol/L rapamycin. Cells were harvested and the Akt kinase assay from Cell Signaling Technology was used. Akt1 was immunoprecipitated from lysates and used in an in vitro kinase assay to catalyze phosphorylation of a GSK-3 fusion protein (1 µg) in the presence of 200 µmol/L ATP. The reaction product was subjected to SDS-PAGE and probed with p-GSK3/ß antibody (S21/9).

Human solid tumor biopsy and immunohistochemistry. Tumor biopsies from patients treated with RAD001 were analyzed. Patients were treated with RAD001 administered p.o. daily (10 mg, four patients) or weekly (50 mg, four patients). Sequential tumor biopsies at baseline time point—prior to start treatment—and 28 days after therapy were done in all patients. All tissue specimens were fixed in 10% buffered neutral formalin for 24 hours at room temperature, then dehydrated and paraffin embedded. Immunostaining was done on 4 µm tissue sections placed on charged plus glass slides. After deparaffinization in xylene and graded alcohols, heat antigen retrieval was done in citrate buffer (pH 6) for 5 minutes in an autoclave. Following epitope retrieval, endogenous peroxidase was blocked by immersing the sections in 0.03% hydrogen peroxide for 10 minutes. Slides were washed for 5 minutes with TBS. Incubation with polyclonal anti-S473 pAkt antibody was made at room temperature for 2 hours at 1:50 dilution on 0.05 mol/L Tris-HCl buffer [DakoCytomation (Carpinteria, CA) Antibody Diluent]. The peroxidase-labeled polymer conjugated to goat anti-rabbit method was used to detect antigen-antibody reaction (DakoCytomation EnVision+ System) for 30 minutes at room temperature. Sections were then visualized with 3,3'-diaminobenzidine as a chromogen for 5 minutes and counterstained with Mayer's hematoxylin. All immunohistochemical stainings were done in a Dako Autostainer under the same conditions. The same sections incubated with rabbit nonimmunized serum were used as negative controls; for the positive control, sections of a breast carcinoma human tumor with a known expression of pAkt by immunohistochemistry and Western blot were stained. Tumor sections were studied on a light microscope with an ocular magnification of x400. To score a tumor cell as positive for pAkt, nuclear and cytoplasmic staining was required. The percentage of stained tumor cells was scored in a whole section and the average percentage and intensity of tumor cell staining was calculated as a histoscore as described previously (12). Tumors with >1% of tumor cells staining were considered positive for such markers. Grading of scoring ranged from a score of 0 to 300. Scoring was blinded to time point data. Statistical analysis for Wilcoxon signed ranks test was done between pretherapy and posttherapy levels of pAkt (SPSS analysis software 10.0).

Cell proliferation studies. 100,000 DU-145 or MCF-7 cells, and 50,000 MDA-MB-468 cells were plated in normal growth medium. The cells were grown overnight before treatment with DMSO, 1 nmol/L rapamycin, 1 µmol/L NVP-AEW541, or combined 1 nmol/L rapamycin and 1 µmol/L NVP-AEW541. Cells were trypsinized and counted on a Coulter counter.

Cell cycle analysis. Cells (1 x 10⁶) were plated in 10 cm dishes in normal growth medium and grown overnight before treatment with DMSO, 1 nmol/L rapamycin, or a combination of rapamycin (1 nmol/L) and NVP-AEW541 (1 µmol/L). The nuclei were isolated by the Nusse method (13) and subjected to flow cytometry to determine fraction of cells in sub-G₁, G₁, S, and G₂.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Inhibition of mTOR induces Akt activity in tumor cells. We tested whether inhibition of mTOR caused activation of PI3K/Akt signaling by relieving feedback inhibition of upstream signaling. Prolonged exposure of breast cancer cell lines MCF-7 (PI3K mutant; ref. 14), and MDA-MB-468 (PTEN mutant), or the prostate cancer cell line DU-145 (PTEN wild-type) to the mTOR inhibitor rapamycin caused a marked increase in S473 phosphorylation and Akt kinase activity (Fig. 1A and B). These results are consistent with the recent report by Sun et al. who observed that rapamycin induced pAkt(S473) in several human cancer cell lines including DU-145 and MCF-7 (15). We also observed the induction of pAkt by rapamycin in the breast cancer cell lines, SkBR3 and BT474, cells in which PI3K/Akt is driven by overexpression of human epidermal growth factor receptor 2, and in the rhabdomyosarcoma line Rh30 (Fig. 1C). In DU-145 and MCF-7, induction of S473 phosphorylation occurred within 20 minutes of rapamycin treatment and followed inhibition of mTOR-dependent S6K phosphorylation (Fig. 1A and B). In both cell lines, pAkt was increased 4-fold to 5-fold by 24 hours of rapamycin exposure and remained elevated for at least 48 hours after the addition of the drug. As measured by an in vitro kinase assay, Akt activity in DU-145 increased in parallel with the induction of phosphorylation and was elevated 3-fold compared with controls 4 hours after the addition of the drug (Fig. 1D).

View larger version (82K): [in this window] [in a new window]   Figure 1. mTOR inhibition activates Akt in tumor cells. A, 1 nmol/L rapamycin treatment induced S473 Akt and S21/9 GSK3/ß phosphorylation in vitro in a DU-145 prostate cancer cell line. Akt1, Akt2, and Akt3, total Akt, and total GSK3/ß did not change. Phosphorylation of p70/S6K decreased with rapamycin treatment whereas total p70/S6K levels did not change. B, 1 nmol/L rapamycin treatment induced S473 Akt and S21/9 GSK3/ß phosphorylation in vitro in a MCF-7 cancer cell line. Akt1, Akt2, and Akt3, total Akt, and total GSK3/ß did not change. Phosphorylation of p70/S6K decreased with rapamycin treatment whereas total p70/S6K levels did not change. C, 1 nmol/L rapamycin treatment for 24 hours induced S473 Akt in the breast cancer cell lines BT474, SkBr3, and the rhabdomyosarcoma cell line Rh30. Total Akt levels did not change. D, mTOR inhibition with 1 nmol/L rapamycin induced Akt Kinase activity in an IGF-IR-dependent manner. An Akt kinase assay in DU-145 cells confirmed that the increased pAkt (S473) resulted in increased Akt activity, which was abrogated by the inhibition of PI3K with the small-molecule LY294002 (10 µmol/L) and by inhibition of IGF-IR with either the small-molecule NVP-AEW541 (800 nmol/L) or the monoclonal antibody A12 (10 nmol/L). A Western blot of pAkt (S473) at the same time points in DU-145 showed the increased Akt phosphorylation which was abrogated by IGF-IR or PI3K inhibition. Although there is no detectable increase in pan-phospho-Akt as measured by Western blot, an Akt kinase assay in MDA-MB-468 cells reveals an induction of Akt activity and p-Akt1 (S473) that is abrogated by LY294002 as well as the IGF-IR inhibitors. E, treatment of MCF-7 cells with rapamycin (1 nmol/L) induced phosphorylation of the FoxO transcription factors, FKHR (S256 and T24), AFX (S193), and FKHRL1 (T32). The rapamycin-induced FoxO phosphorylation was abrogated by IGF-IR inhibition with 800 nmol/L NVP-AEW541. Total FKHR, AFX, and FKHRL1 levels did not change with rapamycin or NVP-AEW-541 treatment.

Rapamycin-induced activation of Akt kinase was also associated with increased phosphorylation of endogenous Akt substrates. In MCF-7 cells treated with rapamycin, the phosphorylation of FoxO1a, FoxO3a, and FoxO4 transcription factors (Fig. 1E) and GSK3/ß was markedly increased as compared with control cells (Fig. 1A and B). The increase in GSK3/ß phosphorylation occurred in both DU-145 and MCF-7 cells and began after 40 minutes of rapamycin exposure, remaining elevated for at least 24 hours after initiation of rapamycin treatment. Phosphorylation of FoxO transcription factors was elevated after 1 hour of rapamycin exposure in MCF-7 cells and remained elevated for at least 24 hours. Total FKHR, AFX, and FKHRL1 levels did not change with treatment (Fig. 1E). Thus, rapamycin-induced Akt phosphorylation and kinase activity leads to functional activation of Akt signaling in tumor cells.

Inhibition of mTOR induces S473 Akt phosphorylation in vivo in human tumors. In model systems, tumors with activated Akt secondary to PTEN loss or other causes have been shown to be hypersensitive to rapamycin (16, 17). This data has led to clinical trials of rapamycin derivatives (2, 18). As indicated above, we have shown that mTOR inhibition can activate Akt signaling in tumor cells in tissue culture. To determine if this occurs in patient tumors in vivo as well, we obtained tumor tissue from patients with advanced solid tumors who were being treated on a phase I protocol of the rapamycin derivative RAD001 (Everolimus, Novartis Pharma). The levels of S473 phosphorylated Akt in the tumor biopsies increased after RAD001 treatment (P = 0.018, Wilcoxon signed rank test; Fig. 2A-C). Biopsies of liver metastases or skin lesions were taken from patients with colon or breast carcinoma before and after 4 weeks of RAD001 treatment. The levels of pAkt, as determined by immunohistochemistry and quantitated as a histoscore ranging from 0 to 300, were elevated in biopsies from patients receiving daily RAD001 (n = 4), as well as in biopsies from patients on a weekly dosing schedule (n = 4). Given that Akt activation results in cancer cell survival, proliferation, and growth, the induction of phosphorylated Akt is an unexpected and potentially undesirable consequence of mTOR inhibition.

View larger version (44K): [in this window] [in a new window]   Figure 2. mTOR inhibition activates Akt in humans. A, liver metastasis of a colorectal carcinoma from a patient treated with a daily administration of RAD001 for 4 weeks. pAkt was expressed in nuclei and cytoplasm of tumor cells (1) and levels of expression increased after therapy (2). Skin infiltration by ductal carcinoma in a patient treated with a weekly administration of RAD001 for 4 weeks. A similar increment of pAkt was observed before (3) and after therapy (4); (3,3'-diaminobenzidine, pAkt x400). B, evaluation of levels of pAkt in paired tumor samples from patients treated with daily and weekly administration of RAD001 by immunohistochemistry. A significant increment (P = 0.018) of this protein was observed in eight patients. C, tumor and biopsy characteristics. The characteristics of each tumor biopsy and the dose schedule of the eight patients in the RAD001 clinical trial are described.

View larger version (36K): [in this window] [in a new window]   Figure 3. IGF-I signaling mediates AKT activation induced by mTOR inhibition. A and B, the induction of pAkt (S473) by rapamycin was abrogated by the small-molecule inhibitor of IGF-IR, NVP-AEW541, and by the monoclonal antibody against IGF-IR, A12, in both the DU-145 prostate cancer cell line (A) and the MCF-7 breast cancer cell line (B). Total Akt levels did not change. C, 1 nmol/L rapamycin treatment up-regulates IRS-1 levels in MCF-7, DU-145, and MDA-MB-468 cell lines by 1 hour, and this induction persists for 24 hours. IRS-2 levels remain unchanged.

View larger version (41K): [in this window] [in a new window]   Figure 4. IGF-I prevents and IGF-IR inhibitors enhance the antiproliferative effects of rapamycin. A, IGF-I (60 ng/mL) rescued MCF-7 cells from rapamycin's antiproliferative effects in serum-free medium and the induction of pAKT was greater in cells cotreated with rapamycin and IGF-I than in cells treated with either single agent. B, the combination of mTOR inhibition with IGF-IR inhibition resulted in enhanced antitumor effects. In vitro, combined mTOR and IGF-IR inhibition with rapamycin (1 nmol/L) and NVP-AEW541 (1 µmol/L) resulted in additive inhibition of proliferation in DU-145 cells, MCF-7 cells, and MDA-MB-468 cells as compared with either single agent. C, in the breast cancer cell line, MCF-7, and the prostate cancer cell line, DU-145, 2 days of combined mTOR and IGF-IR inhibition with rapamycin (1 nmol/L) and NVP-AEW541 (1 µmol/L) resulted in enhanced G1 arrest. In the breast cancer cell line, MDA-MB-468, 2 days of combination treatment resulted in enhanced apoptosis compared with single agent treatment groups.

As IGF-I rescued cells from the antiproliferative effects of rapamycin, we tested whether IGF-IR inhibition enhanced the antiproliferative effect of rapamycin in cells growing in serum. Cells were treated with rapamycin, with or without NVP-AEW541, for 3 days. Simultaneous administration of NVP-AEW541 and rapamycin to DU-145, MCF-7, and MDA-MB-468 (Fig. 4B) cancer cells resulted in additive antiproliferative effects as compared with either agent alone. Cell cycle analysis revealed additive effects on G₁ arrest in the MCF-7 and DU-145 cell lines after 2 days of treatment with the combination of IGF-IR and mTOR inhibitors as compared with cells treated with either single agent or vehicle (Fig. 4C). On comparison with control and single agent–treated cells, an enhanced sub-G₁ population was observed in MDA-MB-468 cells after 2 days of treatment with combined mTOR and IGF-IR inhibitors (Fig. 4C).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Dysregulation of mTOR function via physiologic or mutational activation of upstream pathways is a common event in tumors from many lineages (2, 11). We speculated that tumor cells with activated mTOR display a phenotype functionally equivalent to insulin-resistant diabetes with an exaggerated down-regulation of upstream signaling molecules like IRS-1 (4–8). We report here that, in a variety of tumor cell lines, the mTOR inhibitory drug rapamycin up-regulates IRS-1 protein levels and induces Akt phosphorylation, protein kinase activity, and downstream signaling. In parallel clinical studies with the rapamycin derivative RAD001 (Novartis Pharma), the intensity of immunohistochemical staining of tumor biopsies for p-Akt was significantly elevated after 4 weeks of drug treatment. These data suggest that the induction of Akt activity observed in tumor cells in tissue culture is biologically relevant and may be important clinically.

Rapamycin and rapamycin-like molecules inhibit mTOR efficiently in patients, are useful as immunosuppressants, and suppress S6 kinase activity in normal and tumor cells in vitro and in vivo (18). Pharmacologic inhibition of mTOR has been shown to potently inhibit tumor cells with activation of PI3K/Akt signaling due either to PTEN loss, expression of Akt, or growth factor activation (16). In this regard, rapamycin derivatives are effective in in vivo models, as recently shown in myr-Akt-driven transgenic models of prostatic neoplasia (17). The Akt activation induced by rapamycin in tumor cells, however, is likely to reduce its antitumor effects, by activating pathways that attenuate its effects on proliferation and apoptosis. In tumors in which Akt activation is induced, rapamycin will not effectively inhibit PI3K/Akt kinase signaling except insofar as it is mediated through mTOR. We show here that IGF-I overcomes the rapamycin-induced inhibition of MCF-7 proliferation in serum-free medium. This result is consistent with those of Houghton and coworkers, who showed that induction of apoptosis by rapamycin via ASK-1 activation occurs in serum-free but not serum-containing medium (22). We find that inhibition of induction of Akt activation with agents that block IGF-I signaling enhances cell cycle arrest and apoptosis induction by rapamycin.

Despite the results from model systems, the clinical antitumor activity of mTOR inhibitor analogues has been modest at best. Our demonstration that rapamycin can induce Akt phosphorylation in tumors implies that its potential antitumor activity is attenuated by release of feedback inhibition of growth signaling pathways. The results also suggest a new model for the development of effective combinatorial anticancer therapy. Combined inhibition of constitutively activated oncoproteins and of normal pathways that are down-regulated by oncoprotein-inhibition (and thus up-regulated by oncoprotein-targeted drugs) may be much more effective than either alone. For the specific case discussed in this article, the work provides a rationale for tailored combination therapy with an mTOR inhibitor and an inhibitor of the growth factor receptor, such as IGF-IR, that normally drives PI3K activity in that tumor. Considering our results in which LY294002 abrogates rapamycin-induced Akt kinase activity, and the report by Sun et al. detailing the combined efficacy of LY294002 and rapamycin in non–small cell lung cancer cell lines, mTOR inhibitors and PI3K inhibitors might also be a promising combination therapy (15).

We have shown that rapamycin induces Akt activity and that abrogating this induction could enhance the antitumor effects of rapamycin in vitro, but the mechanism of rapamycin-induced Akt activity remains unclear. Our finding that rapamycin treatment induces IRS-1 expression suggests that rapamycin's inhibition of p70/S6K results in increased IGF-IR/IRS-1/PI3K signaling to Akt. Previous reports have shown that p70/S6K mediates phosphorylation of IRS-1 inhibitory serine sites (S312 and/or S636/639) which lead to IRS-1 degradation (8, 23, 24). Thus, suppression of p70 activity by rapamycin may prevent inhibitory IRS-1 phosphorylation, thereby stabilizing IRS-1. An increase in IRS-1 adapter protein levels may induce Akt activity by augmenting IGF-IR signaling to PI3K/Akt. The inhibition of pAkt induction with LY294002 implies that the phenomenon is PI3K-dependent and supports this mechanism. However, LY294002 inhibits several PI3K-like kinases, including mTOR, and has been reported to inhibit the activity of rictor-mTOR, recently described as the Akt S473 kinase/PDK2 (25–27). It is possible that rapamycin, by some unknown mechanism, induces rictor-mTOR activity, resulting in increased S473 Akt levels. These possibilities are currently under investigation.

	Acknowledgments

 
Grant support: NIH grant PO1-CA094060 and the generous support of the Taub Foundation. K.E. O'Reilly was supported by the Medical Scientist Training Program Grant from the NIH.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/17/05. Revised 11/22/05. Accepted 11/30/05.

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				A. Toschi, E. Lee, L. Xu, A. Garcia, N. Gadir, and D. A. Foster Regulation of mTORC1 and mTORC2 Complex Assembly by Phosphatidic Acid: Competition with Rapamycin Mol. Cell. Biol., March 15, 2009; 29(6): 1411 - 1420. [Abstract] [Full Text] [PDF]

				A. Jimeno, W. A. Messersmith, F. R. Hirsch, W. A. Franklin, and S. G. Eckhardt KRAS Mutations and Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: Practical Application of Patient Selection J. Clin. Oncol., March 1, 2009; 27(7): 1130 - 1136. [Abstract] [Full Text] [PDF]

				S. Daouti, H. Wang, W.-h. Li, B. Higgins, K. Kolinsky, K. Packman, A. Specian Jr., N. Kong, N. Huby, Y. Wen, et al. Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy Cancer Res., March 1, 2009; 69(5): 1924 - 1932. [Abstract] [Full Text] [PDF]

				J. Copp, G. Manning, and T. Hunter TORC-Specific Phosphorylation of Mammalian Target of Rapamycin (mTOR): Phospho-Ser2481 Is a Marker for Intact mTOR Signaling Complex 2 Cancer Res., March 1, 2009; 69(5): 1821 - 1827. [Abstract] [Full Text] [PDF]

				M. Marinov, A. Ziogas, O. E. Pardo, L. T. Tan, T. Dhillon, F. A. Mauri, H. A. Lane, N. R. Lemoine, U. Zangemeister-Wittke, M. J. Seckl, et al. AKT/mTOR Pathway Activation and BCL-2 Family Proteins Modulate the Sensitivity of Human Small Cell Lung Cancer Cells to RAD001 Clin. Cancer Res., February 15, 2009; 15(4): 1277 - 1287. [Abstract] [Full Text] [PDF]

				Y. Li, F. Guessous, C. DiPierro, Y. Zhang, T. Mudrick, L. Fuller, E. Johnson, L. Marcinkiewicz, M. Engelhardt, B. Kefas, et al. Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy Mol. Cancer Ther., February 1, 2009; 8(2): 376 - 385. [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]

				J.-Y. Chung, S.-M. Hong, B. Y. Choi, H. Cho, E. Yu, and S. M. Hewitt The Expression of Phospho-AKT, Phospho-mTOR, and PTEN in Extrahepatic Cholangiocarcinoma Clin. Cancer Res., January 15, 2009; 15(2): 660 - 667. [Abstract] [Full Text] [PDF]

				B. M. Wolpin, A. F. Hezel, T. Abrams, L. S. Blaszkowsky, J. A. Meyerhardt, J. A. Chan, P. C. Enzinger, B. Allen, J. W. Clark, D. P. Ryan, et al. Oral mTOR Inhibitor Everolimus in Patients With Gemcitabine-Refractory Metastatic Pancreatic Cancer J. Clin. Oncol., January 10, 2009; 27(2): 193 - 198. [Abstract] [Full Text] [PDF]

				P. A. Dennis Rapamycin for Chemoprevention of Upper Aerodigestive Tract Cancers Cancer Prevention Research, January 1, 2009; 2(1): 7 - 9. [Full Text] [PDF]

				N. T. Ihle and G. Powis Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy Mol. Cancer Ther., January 1, 2009; 8(1): 1 - 9. [Abstract] [Full Text] [PDF]

				G. Desplanques, N. Giuliani, R. Delsignore, V. Rizzoli, R. Bataille, and S. Barille-Nion Impact of XIAP protein levels on the survival of myeloma cells Haematologica, January 1, 2009; 94(1): 87 - 93. [Abstract] [Full Text] [PDF]

				S. R.D. Johnston Role of the mTOR Pathway in Endocrine-resistant Breast Cancer -- Opportunities for Novel Combination Strategies ASCO Educational Book, January 1, 2009; 2009(1): 20 - 28. [Abstract] [Full Text] [PDF]

				A. Bianchini, M. Loiarro, P. Bielli, R. Busa, M. P. Paronetto, F. Loreni, R. Geremia, and C. Sette Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells Carcinogenesis, December 1, 2008; 29(12): 2279 - 2288. [Abstract] [Full Text] [PDF]

				P. J.A. Eichhorn, M. Gili, M. Scaltriti, V. Serra, M. Guzman, W. Nijkamp, R. L. Beijersbergen, V. Valero, J. Seoane, R. Bernards, et al. Phosphatidylinositol 3-Kinase Hyperactivation Results in Lapatinib Resistance that Is Reversed by the mTOR/Phosphatidylinositol 3-Kinase Inhibitor NVP-BEZ235 Cancer Res., November 15, 2008; 68(22): 9221 - 9230. [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]

				M. G. Crespo-Leiro and M. Hermida-Prieto Sirolimus treatment of left ventricular hypertrophy: who, and when? Eur. Heart J., November 2, 2008; 29(22): 2703 - 2704. [Full Text] [PDF]

				S. M. Wilson, D. Barbone, T.-M. Yang, D. M. Jablons, R. Bueno, D. J. Sugarbaker, S. L. Nishimura, G. J. Gordon, and V. C. Broaddus mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment Spheroids Am. J. Respir. Cell Mol. Biol., November 1, 2008; 39(5): 576 - 583. [Abstract] [Full Text] [PDF]

				E. Buck, A. Eyzaguirre, M. Rosenfeld-Franklin, S. Thomson, M. Mulvihill, S. Barr, E. Brown, M. O'Connor, Y. Yao, J. Pachter, et al. Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors Cancer Res., October 15, 2008; 68(20): 8322 - 8332. [Abstract] [Full Text] [PDF]

				R. Chaisuparat, J. Hu, B. C. Jham, Z. A. Knight, K. M. Shokat, and S. Montaner Dual Inhibition of PI3K{alpha} and mTOR as an Alternative Treatment for Kaposi's Sarcoma Cancer Res., October 15, 2008; 68(20): 8361 - 8368. [Abstract] [Full Text] [PDF]

				V. Serra, B. Markman, M. Scaltriti, P. J.A. Eichhorn, V. Valero, M. Guzman, M. L. Botero, E. Llonch, F. Atzori, S. Di Cosimo, et al. NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations Cancer Res., October 1, 2008; 68(19): 8022 - 8030. [Abstract] [Full Text] [PDF]

				S. Ackler, Y. Xiao, M. J. Mitten, K. Foster, A. Oleksijew, M. Refici, S. Schlessinger, B. Wang, S. R. Chemburkar, J. Bauch, et al. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo Mol. Cancer Ther., October 1, 2008; 7(10): 3265 - 3274. [Abstract] [Full Text] [PDF]

				X. Wang, P. Yue, Y. A. Kim, H. Fu, F. R. Khuri, and S.-Y. Sun Enhancing Mammalian Target of Rapamycin (mTOR)-Targeted Cancer Therapy by Preventing mTOR/Raptor Inhibition-Initiated, mTOR/Rictor-Independent Akt Activation Cancer Res., September 15, 2008; 68(18): 7409 - 7418. [Abstract] [Full Text] [PDF]

				J. C. Yao, A. T. Phan, D. Z. Chang, R. A. Wolff, K. Hess, S. Gupta, C. Jacobs, J. E. Mares, A. N. Landgraf, A. Rashid, et al. Efficacy of RAD001 (Everolimus) and Octreotide LAR in Advanced Low- to Intermediate-Grade Neuroendocrine Tumors: Results of a Phase II Study J. Clin. Oncol., September 10, 2008; 26(26): 4311 - 4318. [Abstract] [Full Text] [PDF]

				J. L. Nakamura, E. Garcia, and R. O. Pieper S6K1 Plays a Key Role in Glial Transformation Cancer Res., August 15, 2008; 68(16): 6516 - 6523. [Abstract] [Full Text] [PDF]

				K.-F. Chen, P.-Y. Yeh, K.-H. Yeh, Y.-S. Lu, S.-Y. Huang, and A.-L. Cheng Down-regulation of Phospho-Akt Is a Major Molecular Determinant of Bortezomib-Induced Apoptosis in Hepatocellular Carcinoma Cells Cancer Res., August 15, 2008; 68(16): 6698 - 6707. [Abstract] [Full Text] [PDF]

				J. R. Mills, Y. Hippo, F. Robert, S. M. H. Chen, A. Malina, C.-J. Lin, U. Trojahn, H.-G. Wendel, A. Charest, R. T. Bronson, et al. mTORC1 promotes survival through translational control of Mcl-1 PNAS, August 5, 2008; 105(31): 10853 - 10858. [Abstract] [Full Text] [PDF]

				K. Stemke-Hale, A. M. Gonzalez-Angulo, A. Lluch, R. M. Neve, W.-L. Kuo, M. Davies, M. Carey, Z. Hu, Y. Guan, A. Sahin, et al. An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer Cancer Res., August 1, 2008; 68(15): 6084 - 6091. [Abstract] [Full Text] [PDF]

				D. Opel, M.-A. Westhoff, A. Bender, V. Braun, K.-M. Debatin, and S. Fulda Phosphatidylinositol 3-Kinase Inhibition Broadly Sensitizes Glioblastoma Cells to Death Receptor- and Drug-Induced Apoptosis Cancer Res., August 1, 2008; 68(15): 6271 - 6280. [Abstract] [Full Text] [PDF]

				T. Shimamura, D. Li, H. Ji, H. J. Haringsma, E. Liniker, C. L. Borgman, A. M. Lowell, Y. Minami, K. McNamara, S. A. Perera, et al. Hsp90 Inhibition Suppresses Mutant EGFR-T790M Signaling and Overcomes Kinase Inhibitor Resistance Cancer Res., July 15, 2008; 68(14): 5827 - 5838. [Abstract] [Full Text] [PDF]

				M. Q. Lacy, M. Alsina, R. Fonseca, M. L. Paccagnella, C. L. Melvin, D. Yin, A. Sharma, M. Enriquez Sarano, M. Pollak, S. Jagannath, et al. Phase I, Pharmacokinetic and Pharmacodynamic Study of the Anti-Insulinlike Growth Factor Type 1 Receptor Monoclonal Antibody CP-751,871 in Patients With Multiple Myeloma J. Clin. Oncol., July 1, 2008; 26(19): 3196 - 3203. [Abstract] [Full Text] [PDF]

				A. Soni, A. Akcakanat, G. Singh, D. Luyimbazi, Y. Zheng, D. Kim, A. Gonzalez-Angulo, and F. Meric-Bernstam eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling Mol. Cancer Ther., July 1, 2008; 7(7): 1782 - 1788. [Abstract] [Full Text] [PDF]

				A. Sekulic, P. Haluska Jr, A. J. Miller, J. G. De Lamo, S. Ejadi, J. S. Pulido, D. R. Salomao, E. C. Thorland, R. G. Vile, D. L. Swanson, et al. Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape Mayo Clin. Proc., July 1, 2008; 83(7): 825 - 846. [Abstract] [Full Text] [PDF]

				S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chene, A. De Pover, K. Schoemaker, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity Mol. Cancer Ther., July 1, 2008; 7(7): 1851 - 1863. [Abstract] [Full Text] [PDF]

				C. Tarn, L. Rink, E. Merkel, D. Flieder, H. Pathak, D. Koumbi, J. R. Testa, B. Eisenberg, M. von Mehren, and A. K. Godwin Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors PNAS, June 17, 2008; 105(24): 8387 - 8392. [Abstract] [Full Text] [PDF]

				H. C. Dan, M. J. Cooper, P. C. Cogswell, J. A. Duncan, J. P.-Y. Ting, and A. S. Baldwin Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK Genes & Dev., June 1, 2008; 22(11): 1490 - 1500. [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]

				K. K. Mann, M. Colombo, and W. H. Miller Jr. Arsenic trioxide decreases AKT protein in a caspase-dependent manner Mol. Cancer Ther., June 1, 2008; 7(6): 1680 - 1687. [Abstract] [Full Text] [PDF]

				H. M.W. Verheul, B. Salumbides, K. Van Erp, H. Hammers, D. Z. Qian, T. Sanni, P. Atadja, and R. Pili Combination Strategy Targeting the Hypoxia Inducible Factor-1{alpha} with Mammalian Target of Rapamycin and Histone Deacetylase Inhibitors Clin. Cancer Res., June 1, 2008; 14(11): 3589 - 3597. [Abstract] [Full Text] [PDF]

				L. Meikle, K. Pollizzi, A. Egnor, I. Kramvis, H. Lane, M. Sahin, and D. J. Kwiatkowski Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function J. Neurosci., May 21, 2008; 28(21): 5422 - 5432. [Abstract] [Full Text] [PDF]

				G. Johansson, Y. Y. Mahller, M. H. Collins, M.-O. Kim, T. Nobukuni, J. Perentesis, T. P. Cripe, H. A. Lane, S. C. Kozma, G. Thomas, et al. Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors Mol. Cancer Ther., May 1, 2008; 7(5): 1237 - 1245. [Abstract] [Full Text] [PDF]

				K. H. Lu, W. Wu, B. Dave, B. M. Slomovitz, T. W. Burke, M. F. Munsell, R. R. Broaddus, and C. L. Walker Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma Clin. Cancer Res., May 1, 2008; 14(9): 2543 - 2550. [Abstract] [Full Text] [PDF]

				N. Rhodes, D. A. Heerding, D. R. Duckett, D. J. Eberwein, V. B. Knick, T. J. Lansing, R. T. McConnell, T. M. Gilmer, S.-Y. Zhang, K. Robell, et al. Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity Cancer Res., April 1, 2008; 68(7): 2366 - 2374. [Abstract] [Full Text] [PDF]

				A. O'Donnell, S. Faivre, H. A. Burris III, D. Rea, V. Papadimitrakopoulou, N. Shand, H. A. Lane, K. Hazell, U. Zoellner, J. M. Kovarik, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With Advanced Solid Tumors J. Clin. Oncol., April 1, 2008; 26(10): 1588 - 1595. [Abstract] [Full Text] [PDF]

				J. Tabernero, F. Rojo, E. Calvo, H. Burris, I. Judson, K. Hazell, E. Martinelli, S. R. y Cajal, S. Jones, L. Vidal, et al. Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors J. Clin. Oncol., April 1, 2008; 26(10): 1603 - 1610. [Abstract] [Full Text] [PDF]

				D. Zhong, X. Liu, K. Schafer-Hales, A. I. Marcus, F. R. Khuri, S.-Y. Sun, and W. Zhou 2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition Mol. Cancer Ther., April 1, 2008; 7(4): 809 - 817. [Abstract] [Full Text] [PDF]

				P. C. McDonald, A. Oloumi, J. Mills, I. Dobreva, M. Maidan, V. Gray, E. D. Wederell, M. B. Bally, L. J. Foster, and S. Dedhar Rictor and Integrin-Linked Kinase Interact and Regulate Akt Phosphorylation and Cancer Cell Survival Cancer Res., March 15, 2008; 68(6): 1618 - 1624. [Abstract] [Full Text] [PDF]

				D. Kong, S. Banerjee, W. Huang, Y. Li, Z. Wang, H.-R. C. Kim, and F. H. Sarkar Mammalian Target of Rapamycin Repression by 3,3'-Diindolylmethane Inhibits Invasion and Angiogenesis in Platelet-Derived Growth Factor-D-Overexpressing PC3 Cells Cancer Res., March 15, 2008; 68(6): 1927 - 1934. [Abstract] [Full Text] [PDF]

				A. Moreno, A. Akcakanat, M. F Munsell, A. Soni, J. C Yao, and F. Meric-Bernstam Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors Endocr. Relat. Cancer, March 1, 2008; 15(1): 257 - 266. [Abstract] [Full Text] [PDF]

				B. Hegedus, D. Banerjee, T.-H. Yeh, S. Rothermich, A. Perry, J. B. Rubin, J. R. Garbow, and D. H. Gutmann Preclinical Cancer Therapy in a Mouse Model of Neurofibromatosis-1 Optic Glioma Cancer Res., March 1, 2008; 68(5): 1520 - 1528. [Abstract] [Full Text] [PDF]

				S. H. Oh, Q. Jin, E. S. Kim, F. R. Khuri, and H.-Y. Lee Insulin-like Growth Factor-I Receptor Signaling Pathway Induces Resistance to the Apoptotic Activities of SCH66336 (Lonafarnib) through Akt/Mammalian Target of Rapamycin-Mediated Increases in Survivin Expression Clin. Cancer Res., March 1, 2008; 14(5): 1581 - 1589. [Abstract] [Full Text] [PDF]

				A. A. Brandes, E. Franceschi, A. Tosoni, M. E. Hegi, and R. Stupp Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments Clin. Cancer Res., February 15, 2008; 14(4): 957 - 960. [Abstract] [Full Text] [PDF]

				M.-E. Legrier, C.-P. H. Yang, H.-G. Yan, L. Lopez-Barcons, S. M. Keller, R. Perez-Soler, S. B. Horwitz, and H. M. McDaid Targeting Protein Translation in Human Non Small Cell Lung Cancer via Combined MEK and Mammalian Target of Rapamycin Suppression Cancer Res., December 1, 2007; 67(23): 11300 - 11308. [Abstract] [Full Text] [PDF]

				X. Wang, P. Yue, C.-B. Chan, K. Ye, T. Ueda, R. Watanabe-Fukunaga, R. Fukunaga, H. Fu, F. R. Khuri, and S.-Y. Sun Inhibition of Mammalian Target of Rapamycin Induces Phosphatidylinositol 3-Kinase-Dependent and Mnk-Mediated Eukaryotic Translation Initiation Factor 4E Phosphorylation Mol. Cell. Biol., November 1, 2007; 27(21): 7405 - 7413. [Abstract] [Full Text] [PDF]

				M. Fouladi, F. Laningham, J. Wu, M. A. O'Shaughnessy, K. Molina, A. Broniscer, S. L. Spunt, I. Luckett, C. F. Stewart, P. J. Houghton, et al. Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors J. Clin. Oncol., October 20, 2007; 25(30): 4806 - 4812. [Abstract] [Full Text] [PDF]

				G. A. Finlay, A. J. Malhowski, Y. Liu, B. L. Fanburg, D. J. Kwiatkowski, and D. Toksoz Selective Inhibition of Growth of Tuberous Sclerosis Complex 2 Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase Function and Reduced mTOR/S6 Kinase Activity Cancer Res., October 15, 2007; 67(20): 9878 - 9886. [Abstract] [Full Text] [PDF]

				C.-H. Lu, S. L. Wyszomierski, L.-M. Tseng, M.-H. Sun, K.-H. Lan, C. L. Neal, G. B. Mills, G. N. Hortobagyi, F. J. Esteva, and D. Yu Preclinical Testing of Clinically Applicable Strategies for Overcoming Trastuzumab Resistance Caused by PTEN Deficiency Clin. Cancer Res., October 1, 2007; 13(19): 5883 - 5888. [Abstract] [Full Text] [PDF]

				X. Q. Lun, H. Zhou, T. Alain, B. Sun, L. Wang, J. W. Barrett, M. M. Stanford, G. McFadden, J. Bell, D. L. Senger, et al. Targeting Human Medulloblastoma: Oncolytic Virotherapy with Myxoma Virus Is Enhanced by Rapamycin Cancer Res., September 15, 2007; 67(18): 8818 - 8827. [Abstract] [Full Text] [PDF]

				E. L. Kwak, J. W. Clark, and B. Chabner Targeted Agents: The Rules of Combination Clin. Cancer Res., September 15, 2007; 13(18): 5232 - 5237. [Abstract] [Full Text] [PDF]

				E. K. Rowinsky, H. Youssoufian, J. R. Tonra, P. Solomon, D. Burtrum, and D. L. Ludwig IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor Clin. Cancer Res., September 15, 2007; 13(18): 5549s - 5555s. [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]

				G. J. Riely, M. G. Kris, B. Zhao, T. Akhurst, D. T. Milton, E. Moore, L. Tyson, W. Pao, N. A. Rizvi, L. H. Schwartz, et al. Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Everolimus Clin. Cancer Res., September 1, 2007; 13(17): 5150 - 5155. [Abstract] [Full Text] [PDF]

				A. B. Hjelmeland, K. P. Lattimore, B. E. Fee, Q. Shi, S. Wickman, S. T. Keir, M. D. Hjelmeland, D. Batt, D. D. Bigner, H. S. Friedman, et al. The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion Mol. Cancer Ther., September 1, 2007; 6(9): 2449 - 2457. [Abstract] [Full Text] [PDF]

				L. M. Ballou, E. S. Selinger, J. Y. Choi, D. G. Drueckhammer, and R. Z. Lin Inhibition of Mammalian Target of Rapamycin Signaling by 2-(Morpholin-1-yl)pyrimido[2,1-{alpha}]isoquinolin-4-one J. Biol. Chem., August 17, 2007; 282(33): 24463 - 24470. [Abstract] [Full Text] [PDF]

				J. A. Crowell, V. E. Steele, and J. R. Fay Targeting the AKT protein kinase for cancer chemoprevention Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148. [Abstract] [Full Text] [PDF]

				J. D. Mosley, J. T. Poirier, D. D. Seachrist, M. D. Landis, and R. A. Keri Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer Mol. Cancer Ther., August 1, 2007; 6(8): 2188 - 2197. [Abstract] [Full Text] [PDF]

				I Duran, R Salazar, O Casanovas, V Arrazubi, E Vilar, L. Siu, J Yao, and J Tabernero New drug development in digestive neuroendocrine tumors Ann. Onc., August 1, 2007; 18(8): 1307 - 1313. [Abstract] [Full Text] [PDF]

				T. C. Vary, G. Deiter, and C. J. Lynch Rapamycin Limits Formation of Active Eukaryotic Initiation Factor 4F Complex Following Meal Feeding in Rat Hearts J. Nutr., August 1, 2007; 137(8): 1857 - 1862. [Abstract] [Full Text] [PDF]

				B. E. Johnson, D. Jackman, and P. A. Janne Rationale for a Phase I Trial of Erlotinib and the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) for Patients with Relapsed Non Small Cell Lung Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4628s - 4631s. [Abstract] [Full Text] [PDF]

				J. A. Engelman The Role of Phosphoinositide 3-Kinase Pathway Inhibitors in the Treatment of Lung Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4637s - 4640s. [Abstract] [Full Text] [PDF]

				X. Wan and L. J. Helman The Biology Behind mTOR Inhibition in Sarcoma Oncologist, August 1, 2007; 12(8): 1007 - 1018. [Abstract] [Full Text] [PDF]

				F. M. Johnson, B. Saigal, H. Tran, and N. J. Donato Abrogation of Signal Transducer and Activator of Transcription 3 Reactivation after Src Kinase Inhibition Results in Synergistic Antitumor Effects Clin. Cancer Res., July 15, 2007; 13(14): 4233 - 4244. [Abstract] [Full Text] [PDF]

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				R. T. Abraham and J. J. Gibbons The Mammalian Target of Rapamycin Signaling Pathway: Twists and Turns in the Road to Cancer Therapy Clin. Cancer Res., June 1, 2007; 13(11): 3109 - 3114. [Abstract] [Full Text] [PDF]

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