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The PI3K/AKT/mTOR Signaling Pathway: Implications in the Treatment of Breast Cancer

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Abstract

Epidemiologic and experimental studies support a key role of the phosphatidyl inositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the biology of human cancers. Alterations resulting in activation of PI3K/Akt/mTOR signaling are perhaps the most frequent events observed in solid tumors, including breast cancer, and contribute to neoplastic transformation. The PI3K/mTOR pathway can be activated by overproduction of growth factors or chemokines, loss of phosphatase and tensin homolog (PTEN) expression, or by mutations in growth factor receptors Ras, PTEN, or PI3K itself. Activation of this pathway contributes to cell cycle proliferation, growth, cell cycle entry, survival, cell motility, protein synthesis, and glucose metabolism, all important aspects of tumorigenesis. The most common genetic aberrations in breast cancer are activating somatic missense mutations in the gene encoding the p110a (PIK3CA) subunit of PI3K. The PTEN gene is often hypermethylated or decreased in expression, through as yet unclear mechanisms, in breast cancer. Studies have shown that PI3K/PTEN/AKT pathway modulation is implicated in HER2/neu-tumorigenesis and in response to the HER2-targeting antibody trastuzumab. Components of the pathway are regulated by feed-back and cross-talk to other signaling cascades and appear to be implicated with drug resistance. Over the past few years, a number of components of this signaling cascade have been the subject of intense drug-discovery activities. Rapamycin analogs have already been shown to have antitumor efficacy in some tumor types. Newer-generation PI3K, AKT, and mTOR inhibitors have shown significant promise preclinically and are now in clinical trials. This article summarizes the progress made in the elucidation of the pathway, clinical implications in pathology of breast cancer, and reviews novel drugs targeting this pathway for cancer treatment, particularly inhibitors of PI3K, AKT, and mTOR, currently undergoing clinical trials. Potential combination strategies, safety concerns, and resistance mechanisms for this new generation of anticancer agents are also discussed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Yuan TL, Cantley LC: PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497–510, 2008

    Article  CAS  PubMed  Google Scholar 

  2. Crabbe T, Welham MJ, Ward SG: The PI3K inhibitor arsenal: choose your weapon! Trends Biochem Sci 32:450–6, 2007

    Article  CAS  PubMed  Google Scholar 

  3. Chalhoub N, Baker SJ: PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127–50, 2009

    Article  CAS  PubMed  Google Scholar 

  4. • Samuels Y, Wang Z, Bardelli A, et al: High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554, 2004. This is an excellent review of the oncogenic PI3K mutations in human cancers.

    Article  CAS  PubMed  Google Scholar 

  5. Zhao L, Vogt PK: Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–96, 2008

    Article  CAS  PubMed  Google Scholar 

  6. Zhou BP, Hu MC, Miller SA, et al: HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. J Biol Chem 275:8027–31, 2000

    Article  CAS  PubMed  Google Scholar 

  7. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al: An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–91, 2008

    Article  CAS  PubMed  Google Scholar 

  8. Cui X, Zhang P, Deng W, et al: Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol Endocrinol 17:575–88, 2003

    Article  CAS  PubMed  Google Scholar 

  9. Chung J, Bachelder RE, Lipscomb EA, et al: Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. J Cell Biol 158:165–74, 2002

    Article  CAS  PubMed  Google Scholar 

  10. Stiles BL: Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. Int J Biochem Cell Biol 41:757–61, 2009

    Article  CAS  PubMed  Google Scholar 

  11. Trotman LC, Pandolfi PP: PTEN and p53: who will get the upper hand? Cancer Cell 3:97–9, 2003

    Article  CAS  PubMed  Google Scholar 

  12. Bhaskar PT, Hay N: The two TORCs and Akt. Dev Cell 12:487–502, 2007

    Article  CAS  PubMed  Google Scholar 

  13. De Benedetti A, Graff JR: eIF-4E expression and its role in malignancies and metastases. Oncogene 23:3189–99, 2004

    Article  PubMed  Google Scholar 

  14. Soni A, Akcakanat A, Singh G, et al: eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Mol Cancer Ther 7:1782–8, 2008

    Article  CAS  PubMed  Google Scholar 

  15. Maurer M, Su T, Saal LH, et al: 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res 69:6299–306, 2009

    Article  CAS  PubMed  Google Scholar 

  16. Saal LH, Holm K, Maurer M, et al: PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–9, 2005

    Article  CAS  PubMed  Google Scholar 

  17. Lai YL, Mau BL, Cheng WH, et al: PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol 15:1064–9, 2008

    Article  PubMed  Google Scholar 

  18. Li SY, Rong M, Grieu F, et al: PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 96:91–5, 2006

    Article  CAS  PubMed  Google Scholar 

  19. Kalinsky K, Jacks LM, Heguy A, et al: PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 15:5049–59, 2009

    Article  CAS  PubMed  Google Scholar 

  20. Barbareschi M, Buttitta F, Felicioni L, et al: Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:6064–9, 2007

    Article  CAS  PubMed  Google Scholar 

  21. • Loi S, Haibe-Kains B, Majjaj S, et al: PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A 107:10208–13, 2010. This article reports on genomic and proteomic data predictive value and implications in clinical development of PI3K/mTOR inhibitors.

    Article  CAS  PubMed  Google Scholar 

  22. Whyte DB, Holbeck SL: Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem Biophys Res Commun 340:469–75, 2006

    Article  CAS  PubMed  Google Scholar 

  23. Maruyama N, Miyoshi Y, Taguchi T, et al: Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res 13:408–14, 2007

    Article  CAS  PubMed  Google Scholar 

  24. Ellis MJ, Lin L, Crowder R, et al: Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 119:379–90, 2010

    Article  CAS  PubMed  Google Scholar 

  25. Osborne CK, Shou J, Massarweh S, et al: Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 11:865 s–70 s, 2005

    CAS  PubMed  Google Scholar 

  26. Paz K, Hemi R, LeRoith D, et al: A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 272:29911–8, 1997

    Article  CAS  PubMed  Google Scholar 

  27. Li J, DeFea K, Roth RA: Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. J Biol Chem 274:9351–6, 1999

    Article  CAS  PubMed  Google Scholar 

  28. Trotman LC, Alimonti A, Scaglioni PP, et al: Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441:523–7, 2006

    Article  CAS  PubMed  Google Scholar 

  29. Bernardi R, Guernah I, Jin D, et al: PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442:779–85, 2006

    Article  CAS  PubMed  Google Scholar 

  30. Loi S, Sotiriou C, Haibe-Kains B, et al: Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer. BMC Med Genomics 2:37, 2009

    Article  PubMed  Google Scholar 

  31. Massarweh S, Osborne CK, Creighton CJ, et al: Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 68:826–33, 2008

    Article  CAS  PubMed  Google Scholar 

  32. Thomas RK, Baker AC, Debiasi RM, et al: High-throughput oncogene mutation profiling in human cancer. Nat Genet 39:347–51, 2007

    Article  CAS  PubMed  Google Scholar 

  33. Wood LD, Parsons DW, Jones S, et al: The genomic landscapes of human breast and colorectal cancers. Science 318:1108–13, 2007

    Article  CAS  PubMed  Google Scholar 

  34. Tokunaga E, Kimura Y, Oki E, et al: Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. Int J Cancer 118:284–9, 2006

    Article  CAS  PubMed  Google Scholar 

  35. Stauffer F, Maira SM, Furet P, et al: Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway. Bioorg Med Chem Lett 18:1027–30, 2008

    Article  CAS  PubMed  Google Scholar 

  36. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–81, 2007

    Article  CAS  PubMed  Google Scholar 

  37. Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314–22, 2005

    Article  CAS  PubMed  Google Scholar 

  38. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–56, 2008

    Article  CAS  PubMed  Google Scholar 

  39. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2630–7, 2009

    Article  CAS  PubMed  Google Scholar 

  40. Bachelot T. BC, Cropet C et al: TAMRAD: A GINECO Randomized Phase II Trial of Everolimus in Combination with Tamoxifen Versus Tamoxifen Alone in Patients (pts) with Hormone-Receptor Positive, HER2 Negative Metastatic Breast Cancer (MBC) with Prior Exposure to Aromatase Inhibitors (AI). Cancer Res 70:S1–6, 2010

    Article  Google Scholar 

  41. Kondapaka SB, Singh SS, Dasmahapatra GP, et al. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2:1093–103, 2003

    CAS  PubMed  Google Scholar 

  42. Hilgard P, Klenner T, Stekar J, et al. D-21266, a new heterocyclic alkylphospholipid with antitumour activity. Eur J Cancer 33:442–6, 1997

    Article  CAS  PubMed  Google Scholar 

  43. Momota H, Nerio E, Holland EC. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65:7429–35, 2005

    Article  CAS  PubMed  Google Scholar 

  44. Nyakern M, Cappellini A, Mantovani I, et al. Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways. Mol Cancer Ther 5:1559–70, 2006

    Article  CAS  PubMed  Google Scholar 

  45. Leighl NB, Dent S, Clemons M, et al. A Phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Treat 108:87–92, 2008

    Article  CAS  PubMed  Google Scholar 

  46. Knowling M, Blackstein M, Tozer R, et al. A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs 24:435–9, 2006

    Article  CAS  PubMed  Google Scholar 

  47. Marsh Rde W, Rocha Lima CM, Levy DE, et al. A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma. Am J Clin Oncol 30:26–31, 2007

    Article  PubMed  Google Scholar 

  48. Blay JY: Updating progress in sarcoma therapy with mTOR inhibitors. Ann Oncol. 2010

  49. Yang L, Dan HC, Sun M, et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 64:4394–9, 2004

    Article  CAS  PubMed  Google Scholar 

  50. Rhodes N, Heerding DA, Duckett DR, et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 68:2366–74, 2008

    Article  CAS  PubMed  Google Scholar 

  51. Bilodeau MT, Balitza AE, Hoffman JM, et al. Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model. Bioorg Med Chem Lett 18:3178–82, 2008

    Article  CAS  PubMed  Google Scholar 

  52. Vlahos CJ, Matter WF, Hui KY, et al. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269:5241–8, 1994

    CAS  PubMed  Google Scholar 

  53. Foster Pea: Potentiating the antitumor effects of chemotherspy with the selective PI3K inhibitor XL147. AACR-NCI-EORTC. 2007

  54. Workman P, Clarke PA, Guillard S, et al. Drugging the PI3 kinome. Nat Biotechnol 24:794–6, 2006

    Article  CAS  PubMed  Google Scholar 

  55. Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926–35, 2004

    Article  CAS  PubMed  Google Scholar 

  56. Mondesire WH, Jian W, Zhang H, et al. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 10:7031–42, 2004

    Article  CAS  PubMed  Google Scholar 

  57. Knuefermann C, Lu Y, Liu B, et al. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22:3205–12, 2003

    Article  CAS  PubMed  Google Scholar 

  58. Brognard J, Clark AS, Ni Y, et al. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:3986–97, 2001

    CAS  PubMed  Google Scholar 

  59. Gupta AK, Cerniglia GJ, Mick R, et al. Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J Radiat Oncol Biol Phys 56:846–53, 2003

    Article  CAS  PubMed  Google Scholar 

  60. Kim D, Dan HC, Park S, et al. AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci 10:975–87, 2005

    Article  CAS  PubMed  Google Scholar 

  61. Stoica GE, Franke TF, Moroni M, et al. Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene 22:7998–8011, 2003

    Article  PubMed  Google Scholar 

  62. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–27, 2004

    Article  CAS  PubMed  Google Scholar 

  63. VanderWeele DJ, Zhou R, Rudin CM. Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther 3:1605–13, 2004

    CAS  PubMed  Google Scholar 

  64. Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res 8:215, 2006

    Article  PubMed  Google Scholar 

  65. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429–40, 2009

    Article  CAS  PubMed  Google Scholar 

  66. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28:1124–30, 2010

    Article  CAS  PubMed  Google Scholar 

  67. Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 69:9330–6, 2009

    Article  CAS  PubMed  Google Scholar 

  68. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138–44, 2010

    Article  CAS  PubMed  Google Scholar 

  69. Isakoff SJ, Engelman JA, Irie HY, et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65:10992–1000, 2005

    Article  CAS  PubMed  Google Scholar 

  70. Hu L, Hofmann J, Lu Y, et al. Inhibition of phosphatidylinositol 3′-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res 62:1087–92, 2002

    CAS  PubMed  Google Scholar 

  71. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402, 2007

    Article  CAS  PubMed  Google Scholar 

  72. O’Regan R. RAD001(everolimus) in combination wth weekly paclitaxel and trastuzumab in patients with HER-2 overexpressing metastatic breast cancer with prior resistance to trastuzumab: amulticentric phase I clinical trial. Cancer Res 69:3119, 2009

    Article  Google Scholar 

  73. Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 120:2406–13, 2010

    Article  CAS  PubMed  Google Scholar 

  74. Kirkegaard T, Witton CJ, McGlynn LM, et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207:139–46, 2005

    Article  CAS  PubMed  Google Scholar 

  75. deGraffenried LA, Friedrichs WE, Russell DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10:8059–67, 2004

    Article  CAS  PubMed  Google Scholar 

  76. Beeram M, Tan QT, Tekmal RR, et al. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 18:1323–8, 2007

    Article  CAS  PubMed  Google Scholar 

  77. Chow LSY JJ, Baselga J et al: Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 97, 2006

  78. Neckers L, Ivy SP. Heat shock protein 90. Curr Opin Oncol 15:419–24, 2003

    Article  CAS  PubMed  Google Scholar 

  79. Song CH, Park SY, Eom KY, et al. Potential prognostic value of heat-shock protein 90 in the presence of phosphatidylinositol-3-kinase overexpression or loss of PTEN, in invasive breast cancers. Breast Cancer Res 12:R20, 2010

    Article  PubMed  Google Scholar 

  80. Gupta S, Ramjaun AR, Haiko P, et al. Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129:957–68, 2007

    Article  CAS  PubMed  Google Scholar 

  81. Yu CF, Liu ZX, Cantley LG. ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem 277:19382–8, 2002

    Article  CAS  PubMed  Google Scholar 

  82. Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286:1741–4, 1999

    Article  CAS  PubMed  Google Scholar 

  83. Hoeflich KP, O’Brien C, Boyd Z, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 15:4649–64, 2009

    Article  CAS  PubMed  Google Scholar 

  84. Mirzoeva OK, Das D, Heiser LM, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 69:565–72, 2009

    Article  CAS  PubMed  Google Scholar 

  85. Pratilas CA, Taylor BS, Ye Q, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A 106:4519–24, 2009

    Article  CAS  PubMed  Google Scholar 

  86. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118:3065–74, 2008

    CAS  PubMed  Google Scholar 

  87. Alessi DR, Cuenda A, Cohen P, et al. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270:27489–94, 1995

    Article  CAS  PubMed  Google Scholar 

  88. Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–46, 2008

    Article  CAS  PubMed  Google Scholar 

  89. Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 22:4456–62, 2004

    Article  CAS  PubMed  Google Scholar 

  90. McDaid HM, Lopez-Barcons L, Grossman A, et al. Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants. Cancer Res 65:2854–60, 2005

    Article  CAS  PubMed  Google Scholar 

  91. Legrier ME, Yang CP, Yan HG, et al. Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. Cancer Res 67:11300–8, 2007

    Article  CAS  PubMed  Google Scholar 

  92. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–68, 1999

    Article  CAS  PubMed  Google Scholar 

  93. Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–6, 2008

    Article  CAS  PubMed  Google Scholar 

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Eleni Andreopoulou reports no potential conflict of interest relevant to this article.

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  1. Department of Medical Oncology, Breast Section Montefiore Medical Center, Albert Einstein College of Medicine, 1825 Eastchester Road, Bronx, NY, 10461, USA

    Eleni Andreopoulou

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Andreopoulou, E. The PI3K/AKT/mTOR Signaling Pathway: Implications in the Treatment of Breast Cancer. Curr Breast Cancer Rep 3, 63–74 (2011). https://doi.org/10.1007/s12609-010-0038-9

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