Current Breast Cancer Reports

, Volume 6, Issue 2, pp 59–70 | Cite as

The PI3K/AKT/MTOR Signaling Pathway: The Role of PI3K and AKT Inhibitors in Breast Cancer

Systemic Therapy (J Cortes, Section Editor)


Breast cancer is the second leading cause of cancer death in women. Targeted therapies are available for HER2-positive and endocrine-sensitive disease while chemotherapy remains the mainstay of treatment for triple-negative breast cancer. The efficacy of all targeted interventions is, however, limited by primary or secondary resistance. Preclinical data show that active PI3K/AKT/mTOR signaling contributes to therapy resistance in HER2-positive and hormone-receptor-positive breast cancer. In line with these preclinical observations, clinical trials such as BOLERO-2 demonstrated a benefit of additional inhibition of mTOR signaling in advanced estrogen-receptor-positive breast cancer patients refractory to prior aromatase-inhibitor therapy. Besides the mTOR, several other proteins involved in the PI3K-pathway serve as potential therapeutic targets, such as PI3K and AKT. In this review, we summarize the current available knowledge and experimental and clinical research results about targeting the PI3K-pathway in breast cancer and, thus, provide the rationale for PI3K- and AKT-inhibitor use in the clinic.


Cancer Breast PI3K MAPK p110 AKT mTOR mTORC1 mTORC2 Rictor Raptor PIK3CA PTEN Resistance Feedback Crosstalk XL147 BKM120 BYL719 BEZ235 INK1117 MK-2206 Rapalogue Everolimus Temsirolimus 


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

  1. 1.
    Anderson WF, Katki HA, Rosenberg PS. Incidence of breast cancer in the United States: current and future trends. J Natl Cancer Inst. 2011;103:1397–402.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Rev Cancer. 2002;2:489–501.CrossRefGoogle Scholar
  3. 3.
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.PubMedCrossRefGoogle Scholar
  4. 4.
    Ghayad SE, Cohen PA. Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. Recent Patents Anti-Cancer Drug Discov. 2010;5:29–57.CrossRefGoogle Scholar
  5. 5.
    Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, et al. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene. 2003;22:3205–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Gillham H, Golding MC, Pepperkok R, Gullick WJ. Intracellular movement of green fluorescent protein-tagged phosphatidylinositol 3-kinase in response to growth factor receptor signaling. J Cell Biol. 1999;146:869–80.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, et al. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci U S A. 2008;105:8292–7.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, et al. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science. 2000;287:1049–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B. Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc Natl Acad Sci U S A. 2007;104:7809–14.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Rordorf-Nikolic T, Van Horn DJ, Chen D, White MF, Backer JM. Regulation of phosphatidylinositol 3’-kinase by tyrosyl phosphoproteins. Full activation requires occupancy of both SH2 domains in the 85-kDa regulatory subunit. J Biol Chem. 1995;270(8):3662–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Yang HW, Shin MG, Lee S, Kim JR, Park WS, Cho KH, et al. Cooperative activation of PI3K by Ras and Rho family small GTPases. Molecul Cell. 2012;47:281–90.CrossRefGoogle Scholar
  12. 12.
    Hawkins PT, Jackson TR, Stephens LR. Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase. Nature. 1992;358:157–9.PubMedCrossRefGoogle Scholar
  13. 13.•
    Bertucci MC, Mitchell CA. Phosphoinositide 3-kinase and INPP4B in human breast cancer. Ann NY Acad Sci. 2013;1280:1–5. The summarized data in this review provides evidence for the role of INPP4B as a negative regulator of PI3K signaling in breast cancer. PubMedCrossRefGoogle Scholar
  14. 14.
    Bellacosa A, Chan TO, Ahmed NN, Datta K, Malstrom S, Stokoe D, et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene. 1998;17:313–25.PubMedCrossRefGoogle Scholar
  15. 15.
    Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997;277(5325):567–70.Google Scholar
  16. 16.
    Markman B, Atzori F, Perez-Garcia J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol. 2010;21:683–91.PubMedCrossRefGoogle Scholar
  17. 17.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.PubMedCrossRefGoogle Scholar
  18. 18.
    Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003;2:339–45.PubMedCrossRefGoogle Scholar
  19. 19.
    Ghayad SE, Vendrell JA, Ben Larbi S, Dumontet C, Bieche I, Cohen PA. Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways. Int J Cancer. 2010;126:545–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Tomlinson DC, Knowles MA, Speirs V. Mechanisms of FGFR3 actions in endocrine resistant breast cancer. Int J Cancer. 2012;130:2857–66.PubMedCrossRefGoogle Scholar
  21. 21.
    Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70:2085–94.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Gallardo A, Lerma E, Escuin D, Tibau A, Munoz J, Ojeda B, et al. Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer. 2012;106:1367–73.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Zhang Y, Moerkens M, Ramaiahgari S, de Bont H, Price L, Meerman J, et al. Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. Breast Cancer Res. 2011;13:R52.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.•
    Serra V, Eichhorn PJ, Garcia-Garcia C, Ibrahim YH, Prudkin L, Sanchez G, et al. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest. 2013;123:2551–63. This preclinical study identified the overexpression of RSK3 or RSK4 as a mechanism of resistance to PI3K/mTOR blockade in breast cancer and provides a strong rationale for combined use of PI3K- and MAPK-inhibitors. PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer. 2004;5:63–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3:224–37.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009;15:5049–59.PubMedCrossRefGoogle Scholar
  28. 28.
    Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–91.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K, et al. PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups. Breast Cancer Res. 2012;14:R28.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Loi S, Michiels S, Lambrechts D, Salgado R, Sirtaine N, Fumagalli D, et al. Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free survival (RFS) in early breast cancer (BC): results from the FinHER trial. ASCO, Meeting Abstracts. May 30, 2012; 507.Google Scholar
  31. 31.•
    Ramirez-Ardila DE, Helmijr JC, Look MP, Lurkin I, Ruigrok-Ritstier K, van Laere S, et al. Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen. Breast Cancer Res Treat. 2013;139:39–49. This retrospective study evaluated the frequency of PIK3CA mutations in primary breast cancer samples and showed that first-line treatment of PIK3CA mutant breast cancer patients with an aromatase-inhibitor is associated with a longer time to progression when compared to wild-type. PubMedCrossRefGoogle Scholar
  32. 32.
    Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, et al. PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer. 2004;112:407–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Garcia JM, Silva J, Pena C, Garcia V, Rodriguez R, Cruz MA, et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chrom Cancer. 2004;41:117–24.PubMedCrossRefGoogle Scholar
  34. 34.
    Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R. Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene. 1998;17:123–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Feilotter HE, Coulon V, McVeigh JL, Boag AH, Dorion-Bonnet F, Duboue B, et al. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer. 1999;79:718–23.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI, Boyd J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res. 1997;57:3657–9.PubMedGoogle Scholar
  37. 37.
    Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–510.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–44.PubMedCrossRefGoogle Scholar
  39. 39.
    Maurer M, Su T, Saal LH, Koujak S, Hopkins BD, Barkley CR, et al. 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res. 2009;69:6299–306.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Data System Rev. 2012;4, CD006243.Google Scholar
  41. 41.
    Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14:737–44.PubMedGoogle Scholar
  42. 42.
    Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639–48.PubMedGoogle Scholar
  43. 43.
    Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol. 2007;18:977–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.PubMedCrossRefGoogle Scholar
  45. 45.
    Molina MA, Saez R, Ramsey EE, Garcia-Barchino MJ, Rojo F, Evans AJ, et al. NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res. 2002;8:347–53.PubMedGoogle Scholar
  46. 46.
    Price-Schiavi SA, Jepson S, Li P, Arango M, Rudland PS, Yee L, et al. Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. Int J Cancer. 2002;99:783–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Wehrman TS, Raab WJ, Casipit CL, Doyonnas R, Pomerantz JH, Blau HM. A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions. Proc Natl Acad Sci U S A. 2006;103:19063–8.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Molec Cancer Therapeut. 2001;1:85–94.Google Scholar
  49. 49.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.PubMedCrossRefGoogle Scholar
  50. 50.
    Hanker AB, Pfefferle AD, Balko JM, Kuba MG, Young CD, Sanchez V, et al. Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A 2013;110(35):14372–7.Google Scholar
  51. 51.
    Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.PubMedCrossRefGoogle Scholar
  52. 52.
    Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011;128:447–56.PubMedCrossRefGoogle Scholar
  53. 53.•
    Baselga J, Cortes J, Alm S, Clark E, Kiermaier A, Ross G, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC). Cancer Res 2012;72(24 suppl):S5-1. In this placebo-controlled phase 3 trial HER2-positive metastatic breast cancer patients received trastuzumab combined with docetaxel with or without pertuzumab and the biomarker analysis identified PIK3CA mutant patients as a poor prognostic group. Google Scholar
  54. 54.
    Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13:224.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Sokolosky ML, Stadelman KM, Chappell WH, Abrams SL, Martelli AM, Stivala F, et al. Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Oncotarget. 2011;2:538–50.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Vilquin P, Villedieu M, Grisard E, Larbi SB, Ghayad SE, Heudel PE, et al. Molecular characterization of anastrozole resistance in breast cancer: pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK-2206 with an aromatase inhibitor. Int J Cancer, 2013;133(7):1589–602.Google Scholar
  57. 57.
    Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009;284:6361–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Yamnik RL, Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS letters. 2010;584:124–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14:1296–302.PubMedCrossRefGoogle Scholar
  60. 60.
    Beeram M, Tan QT, Tekmal RR, Russell D, Middleton A, DeGraffenried LA. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol. 2007;18:1323–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Lu CH, Wyszomierski SL, Tseng LM, Sun MH, Lan KH, Neal CL, et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res. 2007;13:5883–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Liu H, Zang C, Schefe JH, Schwarzlose-Schwarck S, Regierer AC, Elstner E, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to the cytotoxic effect of carboplatin in breast cancer in vitro. Anticancer Res. 2011;31:2713–22.PubMedGoogle Scholar
  63. 63.•
    Baselga J, Campone M, Piccart M, Burris III HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9. The BOLERO-2 trial showed that advanced postmenopausal hormone-receptor-positive breast cancer patients refractory to prior aromatase-inhibitor therapy benefit from the addition of everolimus to an aromatase-inhibitor therapy in terms of increased progression free survival. PubMedCrossRefGoogle Scholar
  64. 64.•
    Burris III HA, Lebrun F, Rugo HS, Beck JT, Piccart M, Neven P, et al. Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane vs placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial. Cancer. 2013;119:1908–15. The assessment of treatment effects in the BOLERO-2 trial provides evidence that the combined use of everolimus and exemestane for the treatment of advanced postmenopausal hormone-receptor-positive breast cancer patients with resistance to aromatase-inhibitors increases the time to deterioration of health-related quality of life. PubMedCrossRefGoogle Scholar
  65. 65.
    Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, Burris HA, Campone M, Noguchi S, et al. Correlation of molecular alterations with efficacy of everolimus in hormone-receptor-positive (HR+), HER2-negative advanced breast cancer: preliminary results from BOLERO-2. ASCO, Meeting Abstracts. Jun 17, 2013;LBA509.Google Scholar
  66. 66.•
    Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30:2718–24. Results from this trial revealed that the combination of tamoxifen and everolimus significantly increases the time to progression in postmenopausal hormone-receptor positive metastatic breast cancer patients who showed resistance to aromatase-inhibitors. PubMedCrossRefGoogle Scholar
  67. 67.
    Treilleux I, Arnedos M, Cropet C, Ferrero JM, Lacourtoisie SA, Spaeth D, et al. Predictive markers of everolimus efficacy in hormone receptor positive (HR+) metastatic breast cancer (MBC): final results of the TAMRAD trial translational study. ASCO, Meeting Abstracts. Jun 17, 2013:510.Google Scholar
  68. 68.•
    Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, 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. 2009;27:2630–7. This study demonstrated that everolimus significantly increases the letrozole efficacy in neoadjuvant therapy of patients with operable hormone-receptor-positive breast cancer. PubMedCrossRefGoogle Scholar
  69. 69.
    Shoma A, Moutamed A, Ameen M, Abdelwahab A. Ultrasound for accurate measurement of invasive breast cancer tumor size. Breast J. 2006;12:252–6.PubMedCrossRefGoogle Scholar
  70. 70.•
    Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol. 2013;31:195–202. Results from this study revealed that the addition of temsirolimus to letrozole does not improve progression-free survival as first-line therapy in patients with aromatase-inhibitor-naive advanced breast cancer. PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.•
    O’Regan RM, Ozguroglu M, Andre F, Toi M, Jerusalem G, Wilks S, et al. Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). ASCO, Meeting Abstracts. Jun 17, 2013:505. The BOLERO-3 trial investigated the impact of combining everolimus with vinorelbine and trastuzumab on progression-free survival in HER2-positive women with advanced breast cancer that were resistant to trastuzumab and pretreated with a taxane. Results could only demonstrate a marginal benefit for the everolimus arm thereby calling the beneficial effect of mTOR-inhibitors in HER2-positive breast cancer into question. Google Scholar
  72. 72.•
    Blackwell KL, Miles D, Gianni L, Krop I, Welslau M, Baselga J, et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. ASCO, Meeting Abstracts. Jun 21, 2012:LBA1. According to this phase III study, trastuzumab-emtansine is more effective than the combination of capecitabine and lapatinib in terms of progression-free survival in trastuzumab-refractory HER2-positive advanced breast cancer patients. Google Scholar
  73. 73.•
    Huober J, Fasching PA, Hanusch C, Rezai M, Eidtmann H, Kittel K, et al. Neoadjuvant chemotherapy with paclitaxel and everolimus in breast cancer patients with nonresponsive tumors to epirubicin/cyclophosphamide (EC) +/- bevacizumab - results of the randomised GeparQuinto study (GBG 44). Eur J Cancer. 2013;49:2284–93. Results from this trial showed that the combination of paclitaxel and everolimus in HER2-negative breast cancer patients nonresponsive to prior chemotherapy does not lead to an increased pathologic complete remission rate when compared to paclitaxel monotherapy. PubMedCrossRefGoogle Scholar
  74. 74.
    Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26:1932–40.PubMedCrossRefGoogle Scholar
  75. 75.
    O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500–8.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Meric-Bernstam F, Akcakanat A, Chen H, Do KA, Sangai T, Adkins F, et al. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res. 2012;18:1777–89.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molec Cell. 2006;22:159–68.PubMedCrossRefGoogle Scholar
  78. 78.
    Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 2011;1:248–59.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Guichard SM, Howard Z, Heathcote D, Roth M, Hughes G, Curwen J, et al. AZD2014, a dual mTORC1 and mTORC2 inhibitor is differentiated from allosteric inhibitors of mTORC1 in ER + breast cancer. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research Chicago, IL. 2012; [Abstract #917 2012].Google Scholar
  80. 80.
    Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284:8023–32.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065–74.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011;13:R21.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmana J, et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2012;2:1048–63.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Kimbung S, Biskup E, Johansson I, Aaltonen K, Ottosson-Wadlund A, Gruvberger-Saal S, et al. Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition. Cancer Lett. 2012;319:232–41.PubMedCrossRefGoogle Scholar
  85. 85.
    Ibrahim YH, Garcia-Garcia C, Serra V, He L, Torres-Lockhart K, Prat A, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012;2:1036–47.PubMedCrossRefGoogle Scholar
  86. 86.
    Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30:282–90.PubMedCrossRefGoogle Scholar
  87. 87.
    Mayer IA, Abramson VG, Balko JM, Isakoff SJ, Kuba MG, Sanders M, et al. SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC). ASCO, Meeting Abstracts. May 30, 2012;510.Google Scholar
  88. 88.•
    Iwata H, Baselga J, Campone M, Arteaga C, Cortes J, Jonat W, et al. Ph III randomized studies of the oral pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer (BC) after aromatase inhibitor (AI; BELLE-2) or AI and mTOR inhibitor (BELLE-3) treatment. ASCO, Meeting Abstracts. Jun 17, 2013:TPS650. Results from the BELLE-2 trial might allow drawing comparison between PI3K- and mTOR-inhibition in hormone-receptor-positive advanced breast cancer patients. Results from the BELLE-3 trial are required to clarify whether advanced hormone-receptor-positive tumors with resistance to aromatase-inhibitors and mTOR-inhibitors will respond to PI3K-inhibitors. Google Scholar
  89. 89.
    D Juric, G Argiles, HA Burris, AM Gonzalez-Angulo, C Saura, C Quadt, et al. Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC). Cancer Res 2012;72(24 Suppl; abstr P6-10-07).Google Scholar
  90. 90.
    Jessen K, Kessler L, Kucharski J, Guo X, Staunton J, Janes M, et al. A potent and selective PI3K inhibitor, INK1117, targets human cancers harboring oncogenic PIK3CA mutations. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; San Francisco, CA. 2011; [Abstract A171].Google Scholar
  91. 91.
    Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, 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. 2008;68:8022–30.PubMedCrossRefGoogle Scholar
  92. 92.
    Krop I, Saura C, Ahnert JR, Becerra C, Britten CD, Isakoff SJ, et al. A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer. ASCO, Meeting Abstracts. May 30, 2012:508.Google Scholar
  93. 93.
    Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL, et al. AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol. 2001;159:431–7.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, et al. Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res. 2001;61:5985–91.PubMedGoogle Scholar
  95. 95.
    Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, et al. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem. 1999;274:21528–32.PubMedCrossRefGoogle Scholar
  96. 96.
    Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res. 2012;18:5816–28.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Gonzalez-Angulo AM, Krop I, Piha-Paul SA, Li Y, Culotta KS, Moulder-Thompson S, et al. Phase Ib Dose escalation and biomarker study of MK-2206 in combination with standard doses of weekly paclitaxel in patients with locally advanced or metastatic solid tumors with an expansion in advanced breast cancer. AACR 103rd Annual Meeting; Chicago, IL. 2012; [Abstract #LB-231].Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Florian Huemer
    • 1
    • 2
  • Rupert Bartsch
    • 1
    • 2
  • Michael Gnant
    • 1
    • 3
  1. 1.Comprehensive Cancer Center ViennaMedical University of ViennaViennaAustria
  2. 2.Department of Medicine IMedical University of ViennaViennaAustria
  3. 3.Department of Surgery and Comprehensive Cancer CenterMedical University of ViennaViennaAustria

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