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Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway

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Abstract

Background

Most targeted anticancer therapies, as well as cytotoxic and radiation therapies, are encumbered by the development of secondary resistance by cancer cells. Resistance is a complex phenomenon involving multiple mechanisms, including activation of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR). Novel strategies to overcome resistance by targeting these signaling pathways are being evaluated.

Methods

PubMed and key cancer congress abstracts were searched until July 2012 for preclinical and clinical data relating to the PI3K/AKT/mTOR pathway and anticancer treatment resistance, and use of PI3K/AKT/mTOR inhibitors in resistant cancer cell lines and patient populations.

Results

Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors, radiation, and cytotoxics. As such, inhibitors of the PI3K/AKT/mTOR pathway are being rapidly evaluated in preclinical models and in clinical studies to determine whether they can restore therapeutic sensitivity when given in combination. In breast cancer, non-small-cell lung cancer, and glioblastoma, we find compelling preclinical evidence to show that inhibitors of PI3K or mTOR can restore sensitivity in resistant cells. Although clinical evidence is less mature, a recent Phase III study with the mTORC1 inhibitor everolimus in patients with advanced breast cancer resistant to aromatase inhibition and several Phase I/II studies with PI3K inhibitors demonstrate proof-of-concept, warranting future clinical evaluation.

Conclusion

Current preclinical and clinical evidence suggest that inhibitors of the PI3K/AKT/mTOR pathway could have utility in combination with other anticancer therapies to circumvent resistance by cancer cells. Multiple clinical studies are ongoing.

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References

  1. Harris CA, Ward RL, Dobbins TA, Drew AK, Pearson S (2011) The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis. Ann Oncol 22:1308–1317

    Article  PubMed  CAS  Google Scholar 

  2. Bareschino MA, Schettino C, Rossi A, Maione P, Sacco PC, Zeppa R, Gridelli C (2011) Treatment of advanced non-small cell lung cancer. J Thorac Dis 3:122–133

    PubMed  Google Scholar 

  3. Davis JM, Navolanic PM, Weinstein-Oppenheimer CR, Steelman LS, Hu W, Konopleva M, Blagosklonny MV, McCubrey JA (2003) Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance. Clin Cancer Res 9:1161–1170

    PubMed  CAS  Google Scholar 

  4. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221–9230

    Article  PubMed  CAS  Google Scholar 

  5. Chen ZS, Aoki S, Komatsu M, Ueda K, Sumizawa T, Furukawa T, Okumura H, Ren XQ, Belinsky MG, Lee K, Kruh GD, Kobayashi M, Akiyama S (2001) Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol A on MRP1 function. Int J Cancer 93:107–113

    Article  PubMed  CAS  Google Scholar 

  6. Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644

    Article  PubMed  CAS  Google Scholar 

  7. Powis G, Berggren M, Gallegos A, Frew T, Hill S, Kozikowski A, Bonjouklian R, Zalkow L, Abraham R, Ashendel C (1995) Advances with phospholipid signalling as a target for anticancer drug development. Acta Biochim Pol 42:395–403

    PubMed  CAS  Google Scholar 

  8. Knight ZA, Shokat KM (2007) Chemically targeting the PI3K family. Biochem Soc Trans 35:245–249

    Article  PubMed  CAS  Google Scholar 

  9. Stein RC (2001) Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. Endocr Relat Cancer 8:237–248

    Article  PubMed  CAS  Google Scholar 

  10. Markman B, Dienstmann R, Tabernero J (2010) Targeting the PI3K/Akt/mTOR pathway—beyond rapalogs. Oncotarget 1:530–543

    PubMed  Google Scholar 

  11. Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28:1075–1083

    Article  PubMed  CAS  Google Scholar 

  12. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562

    Article  PubMed  CAS  Google Scholar 

  13. Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–5496

    Article  PubMed  CAS  Google Scholar 

  14. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 1804:433–439

    Article  PubMed  CAS  Google Scholar 

  15. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    Article  PubMed  CAS  Google Scholar 

  16. Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L, Isola J, Bendahl PO, Rosen N, Hibshoosh H, Ringner M, Borg A, Parsons R (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 104:7564–7569

    Article  PubMed  CAS  Google Scholar 

  17. Fedele CG, Ooms LM, Ho M, Vieusseux J, O’Toole SA, Millar EK, Lopez-Knowles E, Sriratana A, Gurung R, Baglietto L, Giles GG, Bailey CG, Rasko JE, Shields BJ, Price JT, Majerus PW, Sutherland RL, Tiganis T, McLean CA, Mitchell CA (2010) Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci USA 107:22231–22236

    Article  PubMed  CAS  Google Scholar 

  18. Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS, Naing A, Falchook GS, Moroney JW, Piha-Paul SA, Wheler JJ, Moulder SL, Fu S, Kurzrock R (2011) PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther 10:558–565

    Article  PubMed  CAS  Google Scholar 

  19. Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, Fu S, Falchook GS, Hong DS, Garrido-Laguna I, Luthra R, Lee JJ, Lu KH, Kurzrock R (2012) PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 30:777–782

    Article  PubMed  CAS  Google Scholar 

  20. Juric D, Baselga J (2012) Tumor genetic testing for patient selection in phase I clinical trials: the case of PI3K inhibitors. J Clin Oncol 30:765–766

    Article  PubMed  CAS  Google Scholar 

  21. Ihle NT, Lemos R Jr, Wipf P, Yacoub A, Mitchell C, Siwak D, Mills GB, Dent P, Kirkpatrick DL, Powis G (2009) Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 69:143–150

    Article  PubMed  CAS  Google Scholar 

  22. O’Brien C, Wallin JJ, Sampath D, GuhaThakurta D, Savage H, Punnoose EA, Guan J, Berry L, Prior WW, Amler LC, Belvin M, Friedman LS, Lackner MR (2010) Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res 16:3670–3683

    Article  PubMed  Google Scholar 

  23. Tazzari PL, Cappellini A, Ricci F, Evangelisti C, Papa V, Grafone T, Martinelli G, Conte R, Cocco L, McCubrey JA, Martelli AM (2007) Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia 21:427–438

    Article  PubMed  CAS  Google Scholar 

  24. Nahta R, O’Regan RM (2010) Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. Clin Breast Cancer 10(Suppl 3):S72–S78

    Article  PubMed  Google Scholar 

  25. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  26. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127

    Article  PubMed  CAS  Google Scholar 

  27. O’Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O’Donovan N, Slamon DJ (2010) Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther 9:1489–1502

    Article  PubMed  Google Scholar 

  28. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402

    Article  PubMed  CAS  Google Scholar 

  29. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429–440

    Article  PubMed  CAS  Google Scholar 

  30. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–441

    Article  PubMed  CAS  Google Scholar 

  31. Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, Arteaga CL (2007) Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 13:4909–4919

    Article  PubMed  CAS  Google Scholar 

  32. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852–1857

    Article  PubMed  CAS  Google Scholar 

  33. Arribas J, Baselga J, Pedersen K, Parra-Palau JL (2011) p95HER2 and breast cancer. Cancer Res 71:1515–1519

    Article  PubMed  CAS  Google Scholar 

  34. Saez R, Molina MA, Ramsey EE, Rojo F, Keenan EJ, Albanell J, Lluch A, Garcia-Conde J, Baselga J, Clinton GM (2006) p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res 12:424–431

    Article  PubMed  CAS  Google Scholar 

  35. Hernandez-Aya LF, Gonzalez-Angulo AM (2011) Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist 16:404–414

    Article  PubMed  CAS  Google Scholar 

  36. Wang L, Zhang Q, Zhang J, Sun S, Guo H, Jia Z, Wang B, Shao Z, Wang Z, Hu X (2011) PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer 11:248

    Article  PubMed  CAS  Google Scholar 

  37. Gallardo A, Lerma E, Escuin D, Tibau A, Munoz J, Ojeda B, Barnadas A, Adrover E, Sanchez-Tejada L, Giner D, Ortiz-Martinez F, Peiro G (2012) 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 106:1367–1373

    Article  PubMed  CAS  Google Scholar 

  38. Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, Minami H (2010) Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol 21:255–262

    Article  PubMed  CAS  Google Scholar 

  39. De PKR, De N, Leyland-Jones B (2010) In vitro evaluation of dual pan-PI3-kinase/mTOR inhibitor in HER2 overexpressing breast cancer cells. American Association for Cancer Research Congress:[abstract 337]

  40. Cizkova M, Bouchalova K, Trojanec R, Dziechciarkova M, Vacher S, Radova L, Furstova J, Hajduch M, Bieche I, Melichar B, Cwiertka K, Kolar Z (2011) Impact of PIK3CA, PTEN and RPS6 status on lapatinib treatment outcome in advanced-stage breast cancer patients. Cancer Res 70:P2-09-30

    Article  Google Scholar 

  41. Gayle SS, Arnold SL, O’Regan RM, Nahta R (2012) Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anticancer Agents Med Chem 12:151–162

    Article  PubMed  CAS  Google Scholar 

  42. Brunner-Kubath C, Shabbir W, Saferding V, Wagner R, Singer CF, Valent P, Berger W, Marian B, Zielinski CC, Grusch M, Grunt TW (2011) The PI3Kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells. Breast Cancer Res Treat 129:387–400

    Article  PubMed  Google Scholar 

  43. Garcia–Garcia C, Ibrahim YH, Serra V, Calvo MT, Guzman M, Grueso J, Aura C, Perez J, Jessen K, Liu Y, Rommel C, Tabernero J, Baselga J, Scaltriti M (2012) Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 18:2603–2612

    Article  PubMed  Google Scholar 

  44. Andre F, Campone M, O’Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay P, Soria JC, Naughton M, Hurvitz SA (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110–5115

    Article  PubMed  CAS  Google Scholar 

  45. Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP, Kindelberger DW, Coviello J, Sahin AA, Nunez R, Hortobagyi GN, Yu D, Esteva FJ (2011) Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 29:3126–3132

    Article  PubMed  CAS  Google Scholar 

  46. Saura C, Bendell J, Jerusalem G, Graña-Suárez B, Su S, Ru Q, De Buck S, Mills D, Ruquet S, Bosch A, Urruticoechea A, Beck JT, DiTomaso E, Sternberg DW, Massacesi C, Hirawat S, Dirix L, Baselga J (2011) Phase I/II study of BKM120 in combination with trastuzumab in patients with HER2-overexpressing metastatic breast cancer resistant to trastuzumab-containing therapy. San Antonio Breast Cancer Conference:[abstract PD09-03]

  47. Miller TW, Balko JM, Arteaga CL (2011) Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 29:4452–4461

    Article  PubMed  CAS  Google Scholar 

  48. Pancholi S, Lykkesfeldt AE, Hilmi C, Banerjee S, Leary A, Drury S, Johnston S, Dowsett M, Martin LA (2008) ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocr Relat Cancer 15:985–1002

    Article  PubMed  CAS  Google Scholar 

  49. Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R (2008) Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 68:826–833

    Article  PubMed  CAS  Google Scholar 

  50. Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1:707–717

    PubMed  CAS  Google Scholar 

  51. Sokolosky ML, Stadelman KM, Chappell WH, Abrams SL, Martelli AM, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, Steelman LS, McCubrey JA (2011) Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Oncotarget 2:538–550

    PubMed  Google Scholar 

  52. Barone I, Cui Y, Herynk MH, Corona-Rodriguez A, Giordano C, Selever J, Beyer A, Ando S, Fuqua SA (2009) Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway. Cancer Res 69:4724–4732

    Article  PubMed  CAS  Google Scholar 

  53. Cavazzoni A, Bonelli MA, Fumarola C, La Monica S, Airoud K, Bertoni R, Alfieri RR, Galetti M, Tramonti S, Galvani E, Harris AL, Martin LA, Andreis D, Bottini A, Generali D, Petronini PG (2012) Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones. Cancer Lett 323:77–87

    Article  PubMed  CAS  Google Scholar 

  54. Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL, Salisbury JD, Cheng AS, Li L, Abbosh PH, Huang TH, Nephew KP (2006) Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res 66:11954–11966

    Article  PubMed  CAS  Google Scholar 

  55. Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, Rasmussen LM, Riese DJ 2nd, de Cremoux P, Stenvang J, Lykkesfeldt AE (2009) Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat 114:263–275

    Article  PubMed  CAS  Google Scholar 

  56. Massarweh S, Osborne CK, Jiang S, Wakeling AE, Rimawi M, Mohsin SK, Hilsenbeck S, Schiff R (2006) Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res 66:8266–8273

    Article  PubMed  CAS  Google Scholar 

  57. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, Garcia-Echeverria C, Shyr Y, Arteaga CL (2010) Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 120:2406–2413

    Article  PubMed  CAS  Google Scholar 

  58. Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM, Lluch A, Gray JW, Brown PH, Hilsenbeck SG, Osborne CK, Mills GB, Lee AV, Schiff R (2010) Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER + breast cancer. Breast Cancer Res 12:R40

    Article  PubMed  Google Scholar 

  59. Cui X, Zhang P, Deng W, Oesterreich S, Lu Y, Mills GB, Lee AV (2003) 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 17:575–588

    Article  PubMed  CAS  Google Scholar 

  60. Ghayad SE, Bieche I, Vendrell JA, Keime C, Lidereau R, Dumontet C, Cohen PA (2008) mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci 99:1992–2003

    PubMed  CAS  Google Scholar 

  61. Ghayad SE, Vendrell JA, Ben Larbi S, Dumontet C, Bieche I, Cohen PA (2010) Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways. Int J Cancer 126:545–562

    Article  PubMed  CAS  Google Scholar 

  62. Leung E, Kim JE, Rewcastle GW, Finlay GJ, Baguley BC (2011) Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells. Cancer Biol Ther 11:938–946

    Article  PubMed  CAS  Google Scholar 

  63. Ellis MJ, Tao Y, Young O, White S, Proia AD, Murray J, Renshaw L, Faratian D, Thomas J, Dowsett M, Krause A, Evans DB, Miller WR, Dixon JM (2006) Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol 24:3019–3025

    Article  PubMed  CAS  Google Scholar 

  64. De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, Tortora G, D’Agostino D, Caputo F, Cancello G, Montagna E, Malorni L, Zinno L, Lauria R, Bianco AR, De Placido S (2005) A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 11:4741–4748

    Article  PubMed  Google Scholar 

  65. Arpino G, Green SJ, Allred DC, Lew D, Martino S, Osborne CK, Elledge RM (2004) HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. Clin Cancer Res 10:5670–5676

    Article  PubMed  CAS  Google Scholar 

  66. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70:2085–2094

    Article  PubMed  CAS  Google Scholar 

  67. Shoman N, Klassen S, McFadden A, Bickis MG, Torlakovic E, Chibbar R (2005) Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod Pathol 18:250–259

    Article  PubMed  CAS  Google Scholar 

  68. Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, Ellis P, Tutt AN, Gillett CE, Hennessy BT, Mills GB, Phillips WA, Piccart MJ, Speed TP, McArthur GA, Sotiriou C (2010) PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 107:10208–10213

    Article  PubMed  CAS  Google Scholar 

  69. Ellis MJ, Lin L, Crowder R, Tao Y, Hoog J, Snider J, Davies S, DeSchryver K, Evans DB, Steinseifer J, Bandaru R, Liu W, Gardner H, Semiglazov V, Watson M, Hunt K, Olson J, Baselga J (2010) Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 119:379–390

    Article  PubMed  CAS  Google Scholar 

  70. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529

    Article  PubMed  CAS  Google Scholar 

  71. Lee YJ, Cho BC, Jee SH, Moon JW, Kim SK, Chang J, Chung KY, Park IK, Choi SH, Kim JH (2010) Impact of environmental tobacco smoke on the incidence of mutations in epidermal growth factor receptor gene in never-smoker patients with non-small-cell lung cancer. J Clin Oncol 28:487–492

    Article  PubMed  CAS  Google Scholar 

  72. Engelman JA, Settleman J (2008) Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev 18:73–79

    Article  PubMed  CAS  Google Scholar 

  73. Kosaka T, Yamaki E, Mogi A, Kuwano H (2011) Mechanisms of resistance to EGFR TKIs and development of a new generation of drugs in non-small-cell lung cancer. J Biomed Biotechnol 2011:165214

    Article  PubMed  Google Scholar 

  74. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73

    Article  PubMed  Google Scholar 

  75. Kosaka T, Yatabe Y, Endoh H, Yoshida K, Hida T, Tsuboi M, Tada H, Kuwano H, Mitsudomi T (2006) Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 12:5764–5769

    Article  PubMed  CAS  Google Scholar 

  76. Tabara K, Kanda R, Sonoda K, Kubo T, Murakami Y, Kawahara A, Azuma K, Abe H, Kage M, Yoshinaga A, Tahira T, Hayashi K, Arao T, Nishio K, Rosell R, Kuwano M, Ono M (2012) Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. PLoS ONE 7:e41017

    Article  PubMed  CAS  Google Scholar 

  77. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043

    Article  PubMed  CAS  Google Scholar 

  78. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W (2007) MET amplification occurs with or without T790 M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 104:20932–20937

    Article  PubMed  CAS  Google Scholar 

  79. Takeuchi S, Wang W, Li Q, Yamada T, Kita K, Donev IS, Nakamura T, Matsumoto K, Shimizu E, Nishioka Y, Sone S, Nakagawa T, Uenaka T, Yano S (2012) Dual inhibition of Met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer. Am J Pathol 181:1034–1043

    Article  PubMed  CAS  Google Scholar 

  80. Kokubo Y, Gemma A, Noro R, Seike M, Kataoka K, Matsuda K, Okano T, Minegishi Y, Yoshimura A, Shibuya M, Kudoh S (2005) Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA). Br J Cancer 92:1711–1719

    Article  PubMed  CAS  Google Scholar 

  81. Kim SM, Kim JS, Kim JH, Yun CO, Kim EM, Kim HK, Solca F, Choi SY, Cho BC (2010) Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. Cancer Lett 296:150–159

    Article  PubMed  CAS  Google Scholar 

  82. Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, Michel K, Peifer M, Mermel C, Girard L, Peyton M, Gazdar AF, Minna JD, Garraway LA, Kashkar H, Pao W, Meyerson M, Thomas RK (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261

    Article  PubMed  CAS  Google Scholar 

  83. Kim Y, Ko J, Cui ZY, Ahn MJ, Park K (2010) PTEN mutation associated with EGFR TKI de novo resistance. American Association for Cancer Research Congress:[abstract 3608]

  84. Donev IS, Wang W, Yamada T, Li Q, Takeuchi S, Matsumoto K, Yamori T, Nishioka Y, Sone S, Yano S (2011) Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer. Clin Cancer Res 17:2260–2269

    Article  PubMed  CAS  Google Scholar 

  85. Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT, Lifshits E, Chen Z, Maira SM, Garcia-Echeverria C, Wong KK, Engelman JA (2009) Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci USA 106:19503–19508

    Article  PubMed  CAS  Google Scholar 

  86. Li H, Schmid-Bindert G, Wang D, Zhao Y, Yang X, Su B, Zhou C (2011) Blocking the PI3K/AKT and MEK/ERK signaling pathways can overcome gefitinib-resistance in non-small cell lung cancer cell lines. Adv Med Sci 56:275–284

    Article  PubMed  CAS  Google Scholar 

  87. Riely GJ, Kris MG, Zhao B, Akhurst T, Milton DT, Moore E, Tyson L, Pao W, Rizvi NA, Schwartz LH, Miller VA (2007) 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 13:5150–5155

    Article  PubMed  CAS  Google Scholar 

  88. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Google Scholar 

  89. The Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  90. Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, Loeffler JS (2004) The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 22:1926–1933

    Article  PubMed  CAS  Google Scholar 

  91. Kao GD, Jiang Z, Fernandes AM, Gupta AK, Maity A (2007) Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem 282:21206–21212

    Article  PubMed  CAS  Google Scholar 

  92. Prevo R, Deutsch E, Sampson O, Diplexcito J, Cengel K, Harper J, O’Neill P, McKenna WG, Patel S, Bernhard EJ (2008) Class I PI3Kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res 68:5915–5923

    Article  PubMed  CAS  Google Scholar 

  93. Wachsberger P, Lawrence R, Liu Y, Andersen B, Dicker A (2012) Improvement of radiotherapy for glioblastoma by co-targeting PI3K and HSP90. American Association for Cancer Research Congress:[abstract 5719]

  94. Chen JS, Zhou LJ, Entin-Meer M, Yang X, Donker M, Knight ZA, Weiss W, Shokat KM, Haas-Kogan D, Stokoe D (2008) Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7:841–850

    Article  PubMed  CAS  Google Scholar 

  95. Carmo A, Carvalheiro H, Crespo I, Nunes I, Lopes MC (2011) Effect of temozolomide on the U-118 glioma cell line. Oncol Lett 2:1165–1170

    PubMed  CAS  Google Scholar 

  96. Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 11:448–457

    Article  PubMed  CAS  Google Scholar 

  97. Hirose Y, Berger MS, Pieper RO (2001) p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res 61:1957–1963

    PubMed  CAS  Google Scholar 

  98. Hirose Y, Katayama M, Mirzoeva OK, Berger MS, Pieper RO (2005) Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. Cancer Res 65:4861–4869

    Article  PubMed  CAS  Google Scholar 

  99. Caporali S, Levati L, Starace G, Ragone G, Bonmassar E, Alvino E, D’Atri S (2008) AKT is activated in an ataxia-telangiectasia and Rad3-related-dependent manner in response to temozolomide and confers protection against drug-induced cell growth inhibition. Mol Pharmacol 74:173–183

    Article  PubMed  CAS  Google Scholar 

  100. Opel D, Westhoff MA, Bender A, Braun V, Debatin KM, Fulda S (2008) Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res 68:6271–6280

    Article  PubMed  CAS  Google Scholar 

  101. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chene P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, Garcia-Echeverria C, Sellers WR, Voliva CF (2012) Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-Kinase inhibitor. Mol Cancer Ther 11:317–328

    Article  PubMed  CAS  Google Scholar 

  102. Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA, Polley MY, Ozawa T, Berger MS, Aftab DT, Prados MD, Haas-Kogan DA (2011) Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro Oncol 13:384–392

    Article  PubMed  CAS  Google Scholar 

  103. Chen L, Han L, Shi Z, Zhang K, Liu Y, Zheng Y, Jiang T, Pu P, Jiang C, Kang C (2012) LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway. Mol Med Report 5:575–579

    CAS  Google Scholar 

  104. Sarkaria JN, Galanis E, Wu W, Dietz AB, Kaufmann TJ, Gustafson MP, Brown PD, Uhm JH, Rao RD, Doyle L, Giannini C, Jaeckle KA, Buckner JC (2010) Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. Clin Cancer Res 16:5573–5580

    Article  PubMed  CAS  Google Scholar 

  105. Sarkaria JN, Galanis E, Wu W, Peller PJ, Giannini C, Brown PD, Uhm JH, McGraw S, Jaeckle KA, Buckner JC (2011) North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 81:468–475

    Article  PubMed  CAS  Google Scholar 

  106. Isoyama S, Dan S, Nishimura Y, Nakamura N, Kajiwara G, Seki M, Irimura T, Yamori T (2012) Establishment of phosphatidylinositol 3-kinase inhibitor-resistant cancer cell lines and therapeutic strategies for overcoming the resistance. Cancer Sci 103:1955–1960

    Google Scholar 

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Acknowledgments

Medical editorial assistance was provided by Alison Lovibond PhD, funded by Novartis Pharmaceuticals. I also acknowledge Sarah Cannon Research Institute for trial support

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  1. Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA

    Howard A. Burris III

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Burris, H.A. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol 71, 829–842 (2013). https://doi.org/10.1007/s00280-012-2043-3

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  • DOI: https://doi.org/10.1007/s00280-012-2043-3

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