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Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer

  • Review – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

PTEN is an essential tumour suppressor gene which encodes a phosphatase protein that antagonises the PI3K/Akt/mTOR antiapoptotic pathway. Impairment of this tumour suppressor pathway potentially becomes a causal factor for development of malignancies. This review aims to assess current understanding of mechanisms of dysfunction involving the PI3K/PTEN/Akt/mTOR pathway linked to tumorigenesis and evaluate the evidence for targeted therapy directed at this signalling axis.

Methods

Relevant articles in scientific databases were identified using a combination of search terms, including “malignancies”, “targeted therapy”, “PTEN”, and “combination therapy”. These databases included Medline, Embase, Cochrane Review, Pubmed, and Scopus.

Results

PI3K/PTEN expression is frequently deregulated in a majority of malignancies through genetic, epigenetic, and post-transcriptional modifications. This contributes to the upregulation of the PI3K/Akt/mTOR pathway which has been the focus of intense clinical studies. Targeted agents aimed at this pathway offer a novel treatment approach in a variety of haematologic malignancies and solid tumours. Compared to single-agent use, greater response rates were obtained in combination regimens, supporting further investigation of suitable drug combinations in a broad spectrum of malignancies.

Conclusion

Activation of the PI3K/PTEN/Akt/mTOR pathway is implicated both in the pathogenesis of malignancies and development of resistance to anticancer therapies. Therefore, PI3K/Akt/mTOR inhibitors are a promising therapeutic option, in association with systemic cytotoxic and biological therapies, to enable sustained clinical outcomes in cancer treatment. Therapeutic strategies could be tailored according to appropriate biomarkers and patient-specific mutation profiles to maximise benefit of combination therapies.

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References

  • Abubaker J, Bavi PP, Al-Harbi S, Siraj AK, Al-Dayel F, Uddin S, Al-Kuraya K (2007) PIK3CA mutations are mutually exclusive with PTEN loss in diffuse large B-cell lymphoma. Leukemia 21(11):2368–2370. doi:10.1038/sj.leu.2404873

    CAS  PubMed  Google Scholar 

  • Al-Lazikani B, Banerji U, Workman P (2012) Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol 30(7):679–692. doi:10.1038/nbt.2284

    CAS  PubMed  Google Scholar 

  • Alvarez EA, Brady WE, Walker JL, Rotmensch J, Zhou XC, Kendrick JE, Aghajanian C (2013) Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 129(1):22–27. doi:10.1016/j.ygyno.2012.12.022

    CAS  PubMed  Google Scholar 

  • Armstrong AJ, Netto GJ, Rudek MA, Halabi S, Wood DP, Creel PA, Carducci MA (2010) A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. Clin Cancer Res 16(11):3057–3066. doi:10.1158/1078-0432.ccr-10-0124

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bai H, Xu R, Cao Z, Wei D, Wang C (2011) Involvement of miR-21 in resistance to daunorubicin by regulating PTEN expression in the leukaemia K562 cell line. FEBS Letters 585(2):402–408. doi:10.1016/j.febslet.2010.12.027

  • Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Rugo HS (2009) 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(16):2630–2637. doi:10.1200/jco.2008.18.8391

    CAS  PubMed  Google Scholar 

  • Bauman JE, Arias-Pulido H, Lee SJ, Fekrazad MH, Ozawa H, Fertig E, Chung CH (2013) A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol 49(5):L461–L467. doi:10.1016/j.oraloncology.2012.12.016

    Google Scholar 

  • Beck AH, Lee CH, Witten DM, Gleason BC, Edris B, Espinosa I, Marinelli RJ (2010) Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling. Oncogene 29(6):845–854

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bendell JC, Nemunaitis J, Vukelja SJ, Hagenstad C, Campos LT, Hermann RC, Richards DA (2011) Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 29(33):4394–4400. doi:10.1200/jco.2011.36.1980

    CAS  PubMed  Google Scholar 

  • Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, Baselga J (2012) Phase I, Dose-Escalation Study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 30:282–290. doi:10.1200/jco.2011.36.1360

    CAS  PubMed  Google Scholar 

  • Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sougnez C (2011) The genomic complexity of primary human prostate cancer. Nature 470(7333):214–220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bitting RL, Healy P, Creel PA, Turnbull J, Morris K, Wood SY, George DJ (2013) A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. doi:10.1016/j.clgc.2013.11.020

    Google Scholar 

  • Bleeker FE, Felicioni L, Buttitta F, Lamba S, Cardone L, Rodolfo M, Bardelli A (2008) AKT1(E17K) in human solid tumours. Oncogene 27(42):5648–5650. doi:10.1038/onc.2008.170

    CAS  PubMed  Google Scholar 

  • Bowles DW, Ma WW, Senzer N, Brahmer JR, Adjei AA, Davies M, Jimeno A (2013) A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer 109(5):1085–1092. doi:10.1038/bjc.2013.474

    PubMed Central  CAS  PubMed  Google Scholar 

  • Britten CD, Adjei AA, Millham R, Houk BE, Borzillo G, Pierce K, LoRusso PM (2014) Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Invest New Drugs 32(3):510–517. doi:10.1007/s10637-013-0062-5

    CAS  PubMed  Google Scholar 

  • Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Furman RR (2014) Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 123(22):3390–3397. doi:10.1182/blood-2013-11-535047

    CAS  PubMed  Google Scholar 

  • Bryce AH, Rao R, Sarkaria J, Reid JM, Qi Y, Qin R, Haluska P (2012) Phase I study of temsirolimus in combination with EKB-569 in patients with advanced solid tumors. Invest New Drugs 30(5):1934–1941. doi:10.1007/s10637-011-9742-1

    CAS  PubMed  Google Scholar 

  • Buijsen J, Lammering G, Jansen RL, Beets GL, Wals J, Sosef M, Lambin P (2013) Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer. Radiother Oncol 107(2):184–188. doi:10.1016/j.radonc.2013.03.023

    CAS  PubMed  Google Scholar 

  • Burris H, Rodon J, Sharma S, Herbst R, Tabernero J, Infante J, Baselga J (2010) First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patient with advanced solid tumors. J Clin Oncol (Meeting Abstracts) 28:3009

    Google Scholar 

  • Chawla SP, Staddon AP, Baker LH, Schuetze SM, Tolcher AW, D'Amato GZ, Demetri GD (2012) Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 30(1):78–84. doi:10.1200/jco.2011.35.6329

  • Chee KG, Longmate J, Quinn DI, Chatta G, Pinski J, Twardowski P, Lara PN (2007) The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial. Clin Genitourin Cancer 5(7):433–437. doi:10.3816/CGC.2007.n.031

    CAS  PubMed  Google Scholar 

  • Chien AJ, Munster PN, Melisko ME, Rugo HS, Park JW, Goga A, Moasser MM (2014) Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer. J Clin Oncol 32(14):1472–1479. doi:10.1200/jco.2013.52.1161

    CAS  PubMed  Google Scholar 

  • Chinnaiyan P, Won M, Wen PY, Rojiani AM, Wendland M, Dipetrillo TA, Corn BW, Mehta MP (2013) RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 86(5):880–884. doi:10.1002/ijrobp.29254

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cho DC, Hutson TE, Samlowski W, Sportelli P, Somer B, Richards P, Vogelzang NJ (2012) Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy. Cancer 118(24):6055–6062. doi:10.1002/cncr.27668

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Pass M (2010) AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 70(1):288–298. doi:10.1158/0008-5472.can-09-1751

    CAS  PubMed  Google Scholar 

  • Ciunci CA, Perini RF, Avadhani AN, Kang HC, Sun W, Redlinger M, O’Dwyer PJ (2014) Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer. Cancer 120(1):77–85. doi:10.1002/cncr.28294

    CAS  PubMed  Google Scholar 

  • Colombo N, McMeekin DS, Schwartz PE, Sessa C, Gehrig PA, Holloway R, Haluska F (2013) Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 108:1021–1026. doi:10.1038/bjc.2013.59

    PubMed Central  CAS  PubMed  Google Scholar 

  • Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28(6):1075–1083. doi:10.1200/jco.2009.25.3641

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cui M, Augert A, Rongione M, Conkrite K, Parazzoli S, Nikitin AY, MacPherson D (2014) PTEN is a potent suppressor of small cell lung cancer. Mol Cancer Res 12(5):654–659. doi:10.1158/1541-7786.mcr-13-0554

    CAS  PubMed  Google Scholar 

  • Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6(3):184–192. doi:10.1038/nrc1819

    CAS  PubMed  Google Scholar 

  • De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N (2012) The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opinion on Therapeutic Targets 16(S2):S17–S27. doi:10.1517/14728222.2011.639361

    PubMed  Google Scholar 

  • Dear Rachel F, McGeechan K, Jenkins Marisa C, Barratt A, Tattersall Martin HN, Wilcken N (2013) Combination versus sequential single agent chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev. doi:10.1002/14651858.CD008792.pub2

    PubMed  Google Scholar 

  • Deenen MJ, Klumpen HJ, Richel DJ, Sparidans RW, Weterman MJ, Beijnen JH, Wilmink JW (2012) Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies. Invest New Drugs 30(4):1557–1565. doi:10.1007/s10637-011-9723-4

    PubMed Central  CAS  PubMed  Google Scholar 

  • Demetri GD, Chawla SP, Ray-Coquard I, LeCesne A, Staddon AP, Milhem MM, Blay JY (2013) Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 31(19):2485–2492. doi:10.1200/jco.2012.45.5766

    CAS  PubMed  Google Scholar 

  • Dolly S, Wagner AJ, Bendell JC, Yan Y, Ware JA, Mazina KE, Holden SN, Derynck MK, De Bono JS, Burris HA (2010) A first-in-human, phase l study to evaluate the dual PI3K/mTOR inhibitor GDC-0980 administered QD in patients with advanced solid tumors or non-Hodgkin’s lymphoma. J Clin Oncol (Meeting Abstracts) 28:3079

    Google Scholar 

  • Fabregas JC, Loaiza-Bonilla A, Talebi TN, Warsch S, Fernandez G, Raez LE, Santos ES (2013) Concurrent chemoradiotherapy versus induction chemotherapy followed by chemoradiotherapy (sequential approach) in the management of head and neck cancer. Expert Rev Anticancer Ther 13(9):1065–1072. doi:10.1586/14737140.2013.829639

    CAS  PubMed  Google Scholar 

  • Fishman MN, Srinivas S, Hauke RJ, Amato RJ, Esteves B, Cotreau MM, Kabbinavar FF (2013) Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. Eur J Cancer 49(13):2841–2850. doi:10.1016/j.ejca.2013.04.019

    CAS  PubMed  Google Scholar 

  • Fleming GF, Ma CX, Huo D, Sattar H, Tretiakova M, Lin L, Ellis MJ (2012) Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 136(2):355–363. doi:10.1007/s10549-011-1910-7

  • Friedman DR, Lanasa MC, Davis PH, Allgood SD, Matta KM, Brander DM, Weinberg JB (2014) Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies. Leuk Lymphoma 55(5):1067–1075. doi:10.3109/10428194.2013.824080

    CAS  PubMed  Google Scholar 

  • Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13(2):140–156. doi:10.1038/nrd4204

  • Fu S, Hennessy Ng, Ju Z, Coombes KR, Wolf JK, Sood AK, Levenback CF, Coleman RL, Kavanagh JJ, Gershenson DM, Markman M, Dice K, Howard A, Li J, Mills GB (2012) Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer. Gynecol Oncol 126(1):47–53. doi:10.1200/go.2099.18754

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gadgeel SM, Lew DL, Synold TW, LoRusso P, Chung V, Christensen SD, Kurzrock R (2013) Phase I study evaluating the combination of lapatinib (a Her2/Neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: South West Oncology Group (SWOG) Study S0528. Cancer Chemother Pharmacol 72(5):1089–1096. doi:10.1007/s00280-013-2297-4

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gallia GL, Rand V, Siu IM, Eberhart CG, James CD, Marie SK, Riggins GJ (2006) PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 4(10):709–714. doi:10.1158/1541-7786.mcr-06-0172

    CAS  PubMed  Google Scholar 

  • Gandhi L, Bahleda R, Tolaney SM, Kwak EL, Cleary JM, Pandya SS, Soria JC (2014) Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol 32(2):68–75. doi:10.1200/jco.2012.47.2787

    CAS  PubMed  Google Scholar 

  • Ganesan P, Piha-Paul S, Naing A, Falchook G, Wheler J, Janku F, Tsimberidou AM (2013) Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer. Invest New Drugs 31(6):1505–1513. doi:10.1007/s10637-013-0013-1

    CAS  PubMed  Google Scholar 

  • Gao Y, Luo LH, Li S, Yang C (2014) miR-17 inhibitor suppressed osteosarcoma tumor growth and metastasis via increasing PTEN expression. Biochem Biophys Res Commun 444(2):230–234. doi:10.1016/j.bbrc.2014.01.061

    CAS  PubMed  Google Scholar 

  • Garrett CR, Coppola D, Wenham RM, Cubitt CL, Neuger AM, Frost TJ, Sebti SM (2011) Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest New Drugs 29(6):1381–1389. doi:10.1007/s10637-010-9479-2

    CAS  PubMed  Google Scholar 

  • Geoerger B, Kieran MW, Grupp S, Perek D, Clancy J, Krygowski M, Spunt SL (2012) Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur J Cancer 48(2):253–262. doi:10.1016/j.ejca.2011.09.021

  • Gibault L, Pérot G, Chibon F, Bonnin S, Lagarde P, Terrier P, Aurias A (2011) New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol 223(1):64–71

    CAS  PubMed  Google Scholar 

  • Glaysher S, Bolton L, Johnson P, Atkey N, Dyson M, Torrance C, Cree I (2013) Targeting EGFR and PI3K pathways in ovarian cancer. Br J Cancer 109(7):1786–1794

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gojo I, Perl A, Luger S, Baer MR, Norsworthy KJ, Bauer KS, Sausville EA (2013) Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome. Invest New Drugs 31(5):1217–1227. doi:10.1007/s10637-013-9937-8

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, Sahin A, Liu S, Barrera JA, Burgues O, Lluch AM, Chen H, Hortobagyi GN (2011) PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther 10(6):1093–1101

    PubMed Central  CAS  PubMed  Google Scholar 

  • Guan X, Vengoechea J, Zheng S, Sloan AE, Chen Y, Brat DJ, Yung WK (2014) Molecular subtypes of glioblastoma are relevant to lower grade glioma. PLoS ONE 9(3):91216

    Google Scholar 

  • Gupta S, Munster P, Hollebecque A (2014) Safety and efficacy of MK-8669 (ridaforolimus) and MK-2206 (AKT inhibitor) in patients with advanced breast cancer with PI3K pathway dependence. Ann Oncol 25:25–27

  • Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y, Look AT (2009) High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 114(3):647–650. doi:10.1182/blood-2009-02-206722

  • Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4(12):988–1004. doi:10.1038/nrd1902

    CAS  PubMed  Google Scholar 

  • Hesson LB, Packham D, Pontzer E, Funchain P, Eng C, Ward RL (2012) A reinvestigation of somatic hypermethylation at the PTEN CpG island in cancer cell lines. Biol Proced 14:5. doi:10.1186/1480-9222-14-5

    CAS  Google Scholar 

  • Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O’Bryant CL, Jimeno A (2012) A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 18(15):4173–4182. doi:10.1158/1078-0432.ccr-12-0714

    CAS  PubMed  Google Scholar 

  • Hopkins BD, Hodakoski C, Barrows D, Mense SM, Parsons RE (2014) PTEN function: the long and the short of it. Trends Biochem Sci 39(4):183–190. doi:10.1016/j.tibs.2014.02.006

  • Hu L, Miao W, Loignon M, Kandouz M, Batist G (2010) Putative chemopreventive molecules can increase Nrf2-regulated cell defense in some human cancer cell lines, resulting in resistance to common cytotoxic therapies. Cancer Chemother Pharmacol 66(3):467–474. doi:10.1007/s00280-009-1182-7

    CAS  PubMed  Google Scholar 

  • Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Bodrogi I (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281. doi:10.1038/nejm.2007.53

    CAS  PubMed  Google Scholar 

  • Hühns M, Salem T, Schneider B, Krohn M, Linnebacher M, Prall F (2014) PTEN mutation, loss of heterozygosity, promoter methylation and expression in colorectal carcinoma: two hits on the gene. Oncol Rep 31(5):2236–2244

    PubMed  Google Scholar 

  • Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Motzer RJ (2014) Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 32(8):760–767. doi:10.1200/jco.2013.50.3961

    CAS  PubMed  Google Scholar 

  • Ihle NT, Powis G (2010) Inhibitors of phosphatidylinositol-3-kinase in cancer therapy. Mol Asp of Med 31(2):135-144. doi:10.1016/j.mam.2010.02.003

  • Jakubowiak AJ, Richardson PG, Zimmerman T, Alsina M, Kaufman JL, Kandarpa M, Anderson KC (2012) Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study. Br J Haematol 158(4):472–480. doi:10.1111/j.1365-2141.2012.09173

    CAS  PubMed  Google Scholar 

  • Jänne PA, Cohen RB, Laird AD, Mace S, Engelman JA, Ruiz-Soto R, Felip E (2014) Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. J Thorac Oncol 9(3):316–323. doi:10.1097/jto.008

    PubMed  Google Scholar 

  • Jerusalem G, Fasolo A, Dieras V, Cardoso F, Bergh J, Vittori L, Gianni L (2011) Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 125(2):447–455. doi:10.1007/s10549-010-1260-x

    CAS  PubMed  Google Scholar 

  • Jokinen E, Laurila N, Koivunen J (2012) Alternative dosing of dual PI3K and MEK inhibition in cancer therapy. BMC Cancer 12(1):612

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kato R, Obara W, Matsuura T, Kato Y, Iwasaki K, Fujioka T (2014) Efficacy of everolimus in patients with advanced renal cell carcinoma refractory or intolerant to VEGFR-TKIs and safety compared with prior VEGFR-TKI treatment. Jpn J Clin Oncol 44(5):479–485. doi:10.1093/jjco/hyu018

    PubMed  Google Scholar 

  • Kechagioglou P, Papi RM, Provatopoulou X, Kalogera E, Papadimitriou E, Grigoropoulos P, Gounaris A (2014) Tumor suppressor PTEN in breast cancer: heterozygosity. Mutat Protein Expr Anticancer Res 34(3):1387–1400

    CAS  Google Scholar 

  • Kelley RK, Nimeiri HS, Munster PN, Vergo MT, Huang Y, Li CM, Venook AP (2013) Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates. Ann Oncol 24(7):1900–1907. doi:10.1093/annonc/mdt109

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kent C, Burris HA, Lowell LH, Kosloff A, Lamar E, John D (2013) Phase I study of the combination of BKM120 and bevacizumab in patients with relapsed/refractory glioblastoma multiforme (GBM) or other refractory solid tumors. J Clin Oncol (Meeting Abstracts) 31:e13045

    Google Scholar 

  • Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, Bose S (2004) PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer 112(3):407–410. doi:10.1002/ijc.20447

    CAS  PubMed  Google Scholar 

  • Kim MS, Jeong EG, Yoo NJ, Lee SH (2008) Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias. Br J Cancer 98(9):1533–1535. doi:10.1038/sj.bjc.6604212

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kita D, Yonekawa Y, Weller M, Ohgaki H (2007) PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol 113(3):295–302. doi:10.1007/s00401-006-0186-1

    CAS  PubMed  Google Scholar 

  • Krohn A, Diedler T, Burkhardt L, Mayer PS, De Silva C, Meyer-Kornblum M, Kotschau D, Tennstedt P, Huang J, Gerhauser C, Mader M, Kurtz S, Sirma H, Saad F, Steuber T, Graefen M, Plass C, Sauter G, Simon R, Minner S, Schlomm T (2012) Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am J Pathol 181(2):401–412

    CAS  PubMed  Google Scholar 

  • Krop IE, Saura C, Rodon JA, Becerra C, Carolyn D, Britten CD, Steven JI, David D, Wolfgang H, Cornelia Q, Antonio PS, Burris HA, Abu-Khalaf MM, Baselga J (2012) 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. J Clin Oncol (Meeting Abstracts) 30:508

    Google Scholar 

  • Kruczek K, Ratterman M, Tolzien K, Sulo S, Lestingi TM, Nabhan C (2013) A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naive castration-resistant prostate cancer. Br J Cancer 109(7):1711–1716. doi:10.1038/bjc.2013.530

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kurman RJ, Shih LM (2011) Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm. Hum Pathol 42(7):918–931. doi:10.1016/j.humpath.2011.03.003

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kwabi-Addo B, Giri D, Schmidt K, Podsypanina K, Parsons R, Greenberg N, Ittmann M (2001) Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci USA 98(20):11563–11568. doi:10.1073/pnas.201167798

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, Pazdur R (2010) FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 15(4):428–435. doi:10.1634/theoncologist.2009-0178

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lang Q, Ling C (2012) MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun 426(2):247–252. doi:10.1016/j.bbrc.2012.08.075

    CAS  PubMed  Google Scholar 

  • Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Lee SH (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24(8):1477–1480. doi:10.1038/sj.onc.1208304

    CAS  PubMed  Google Scholar 

  • Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, Boyd J (2005) Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11(8):2875–2878. doi:10.1158/1078-0432.ccr-04-2142

    CAS  PubMed  Google Scholar 

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947

    CAS  PubMed  Google Scholar 

  • Li YL, Tian Z, Wu DY, Fu BY, Yin Y (2005) Loss of heterozygosity on 10q23.3 and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions. World J Gastroenterol 11(2):285–288

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16(1):64–67

    CAS  PubMed  Google Scholar 

  • Liu L, Zhang W, Li W, Xia Z, Zhang S, Li J (2013a) A phase I study of ridaforolimus in adult Chinese patients with advanced solid tumors. J Hematol Oncol 6:48. doi:10.1186/1756-8722-6-48

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu YE, Lin Q, Meng FJ, Chen XJ, Ren XC, Cao B, Chen Y (2013b) High-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility study. Radiat Oncol 8(1):198. doi:10.1186/1748-717x-8-198

    PubMed Central  PubMed  Google Scholar 

  • Logue JS, Morrison DK (2012) Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Genes Dev 26(7):641–650. doi:10.1101/gad.186965.112

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lopuch S, Kawalec P, Wisniewska N (2014) Effectiveness of targeted therapy as monotherapy or combined therapy in patients with relapsed or refractory multiple myeloma: a systematic review and meta-analysis. Hematology. doi:10.1179/1607845414y.0000000159

    PubMed  Google Scholar 

  • Ma CX, Suman VJ, Goetz M, Haluska P, Moynihan T, Nanda R, Fleming GF (2013) A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 139(1):145–153. doi:10.1007/s10549-013-2528-8

    CAS  PubMed  Google Scholar 

  • Mackay HJ, Eisenhauer EA, Kamel-Reid S, Tsao M, Clarke B, Karakasis K, Oza AM (2014) Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Cancer 120(4):603–610. doi:10.1002/cncr.28414

    CAS  PubMed  Google Scholar 

  • Mahadevan D, Chiorean EG, Harris WB, Von Hoff DD, Stejskal-Barnett A, Qi W, Ramanathan RK (2012) Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur J Cancer 48:3319–3327. doi:10.1016/j.ejca.2012.06.027

  • Malanga D, Scrima M, De Marco C, Fabiani F, De Rosa N, De Gisi S, Viglietto G (2008) Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung. Cell Cycle 7(5):665–669

    CAS  PubMed  Google Scholar 

  • Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, Baselga J (2012) Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 23:2399–2408. doi:10.1093/annonc/mds011

    CAS  PubMed  Google Scholar 

  • Marshall J, Posey J, Hwang J, Malik S, Shen R, Kazempour K, White LR, Fraser KM, Chang CG (2007) A phase I trial of RX-0201 (AKT anti-sense) in patients with an advanced cancer. J Clin Oncol (Meeting Abstracts) 25:3564

    Google Scholar 

  • Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, Kelsey KT (2005) PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 36(7):768–776. doi:10.1016/j.humpath.2005.05.006

    CAS  PubMed  Google Scholar 

  • Martelli AM, Tazzari PL, Evangelisti C, Chiarini F, Blalock WL, Billi AM, Cocco L (2007) Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem 14(19):2009–2023

    CAS  PubMed  Google Scholar 

  • McConechy MK, Ding J, Senz J, Yang W, Melnyk N, Tone AA, Huntsman DG (2014) Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod Pathol 27(1):128–134. doi:10.1038/modpathol.2013.107

  • Meyer LA, Slomovitz BM, Djordjevic B, Westin SN, Iglesias DA, Munsell MF, Lu KH (2014) The search continues: looking for predictive biomarkers for response to Mammalian target of rapamycin inhibition in endometrial cancer. Int J Gynecol Cancer 24(4):713–717. doi:10.1097/igc.000118

    PubMed  Google Scholar 

  • Moelans CB, Verschuur‐Maes AH, van Diest PJ (2011) Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. J Pathol 225(2):222–231

  • Moldovan C, Soria J, LoRusso P, Guthrie T, Song C, Nguyen LT, Martini J, Infante JR, Burris HA (2010) A phase I safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients (pts) with advanced solid tumors. J Clin Oncol (Meeting Abstracts) 28:3070

    Google Scholar 

  • Molife LR, Yan L, Vitfell-Rasmussen J, Zernhelt AM, Sullivan DM, Cassier PA, Minton S (2014) Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol 7:1. doi:10.1186/1756-8722-7-1

    PubMed Central  PubMed  Google Scholar 

  • Molina AM, Hutson TE, Larkin J, Gold AM, Wood K, Carter D, Michaelson MD (2014) A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol 73(1):181–189. doi:10.1007/s00280-013-2339-y

    PubMed Central  CAS  PubMed  Google Scholar 

  • Moreno Garcia V et al (2011) A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma. J Clin Oncol (Meeting Abstracts) 29:3021

    Google Scholar 

  • Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Hollaender N (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma. Cancer 116(18):4256–4265. doi:10.1048/c.2010.42

    CAS  PubMed  Google Scholar 

  • Nagy R, Ganapathi S, Comeras I, Peterson C, Orloff M, Porter K, Kloos RT (2011) Frequency of germline PTEN mutations in differentiated thyroid cancer. Thyroid 21(5):505–510. doi:10.1089/thy.2010.0365

    PubMed Central  CAS  PubMed  Google Scholar 

  • Naing A, Kurzrock R, Burger A, Gupta S, Lei X, Busaidy N, LoRusso P (2011) Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer. Clin Cancer Res 17(18):6052–6060. doi:10.1158/1078-0432.ccr-10-2979

    PubMed Central  CAS  PubMed  Google Scholar 

  • Naing A, Aghajanian C, Raymond E, Olmos D, Schwartz G, Oelmann E, Banerji U (2012) Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer 107(7):1093–1099. doi:10.1038/bjc.2012.368

    PubMed Central  CAS  PubMed  Google Scholar 

  • Negrier S, Gravis G, Perol D, Chevreau C, Delva R, Bay JO, Escudier B (2011) Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol 12(7):673–680. doi:10.1016/s1470-2045(11)70124-3

    CAS  PubMed  Google Scholar 

  • Ng K, Tabernero J, Hwang J, Bajetta E, Sharma S, Del Prete SA, Fuchs CS (2013) Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Clin Cancer Res 19(14):3987–3995. doi:10.1158/1078-0432.ccr-13-0027

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ngeow J, Stanuch K, Mester JL, Barnholtz-Sloan JS, Eng C (2014) Second malignant neoplasms in patients with cowden syndrome with underlying germline PTEN mutations. J Clin Oncol 32(17):1818–1824. doi:10.1200/jco.2013.53.6656

    CAS  PubMed  Google Scholar 

  • Nikiforova MN, Wald AI, Roy S, Durso MB, Nikiforov YE (2013) Targeted next-generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J Clin Endocrinol Metab 98(11):1852–1860

    Google Scholar 

  • Oda K, Stokoe D, Taketani Y, McCormick F (2005) High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 65(23):10669–10673. doi:10.1158/0008-5472.can-05-2620

    CAS  PubMed  Google Scholar 

  • Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Van Cutsem E (2013) Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 31:3935–3943. doi:10.1200/jco.2012.48.3552

    CAS  PubMed  Google Scholar 

  • Okudela K, Suzuki M, Kageyama S, Bunai T, Nagura K, Igarashi H, Sugimura H (2007) PIK3CA mutation and amplification in human lung cancer. Pathol Int 57(10):664–671. doi:10.1111/j.1440-1827.2007.02155.x

    CAS  PubMed  Google Scholar 

  • Pal SK, Reckamp K, Yu H, Figlin RA (2010) Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 19(11):1355–1366. doi:10.1517/13543784.2010.520701

    CAS  PubMed  Google Scholar 

  • Papadopoulos KP, Tabernero J, Markman B, Patnaik A, Tolcher AW, Baselga J, Lorusso PM (2014) Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res 20(9):2445–2456. doi:10.1158/1078-0432.ccr-13-2403

    CAS  PubMed  Google Scholar 

  • Phuong NTT, Kim SK, Lim SC, Kim HS, Kim TH, Lee KY, Ahn SG, Yoon JH, Kang KW (2011) Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells. Breast Cancer Res Treat 130(1):73–83

    CAS  PubMed  Google Scholar 

  • Pires MM, Hopkins BD, Saal LH, Parsons RE (2013) Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells. Cancer Biol Ther 14(3):246–253

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pitz MW, MacNeil MV, Macdonald DR, Kakumanu AS, Thiessen B, Tsao MS, Walsh W (2012) Phase II study of PX-866 in recurrent glioblastoma. J Clin Oncol (Meeting Abstracts) 31:2053

    Google Scholar 

  • Plimack ER, Tan T, Wong YN, von Mehren MM, Malizzia L, Roethke SK, Haas NB (2014) A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma. Oncologist 19(4):354–355. doi:10.1634/theoncologist.2014-0020

    PubMed Central  PubMed  Google Scholar 

  • Price KA, Azzoli CG, Krug LM, Pietanza MC, Rizvi NA, Pao W, Miller VA (2010) Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol 5(10):1623–1629. doi:10.1097/JTO.0b013e3181ec1531

    PubMed Central  PubMed  Google Scholar 

  • Pritchard CC, Smith C, Marushchak T, Koehler K, Holmes H, Raskind W, Walsh T, Bennett RL (2013) A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med 15(12):1004–1007

    CAS  PubMed  Google Scholar 

  • Qi WX, Wang Q, Jiang YL, Sun YJ, Tang LN, He AN, Yao Y (2013) Overall survival benefits for combining targeted therapy as second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of published data. PLoS ONE 8(2):55637. doi:10.1371/journal.pone.0055637

    Google Scholar 

  • Quek R, Wang Q, Morgan JA, Shapiro GI, Butrynski JE, Ramaiya N, George S (2011) Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res 17(4):871–879. doi:10.1158/1078-0432.ccr-10-2621

    CAS  PubMed  Google Scholar 

  • Ray-Coquard I, Favier L, Weber B, Roemer-Becuwe C, Bougnoux P, Fabbro M, Pujade-Lauraine E (2013) Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO. Br J Cancer 108(9):1771–1777. doi:10.1038/bjc.2013.183

    PubMed Central  CAS  PubMed  Google Scholar 

  • Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D, Anderson KC (2011) Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. J Clin Oncol 29(32):4243–4249. doi:10.1200/jco.2010.33.9788

    CAS  PubMed  Google Scholar 

  • Rodon J, Brana I, Siu LL, De Jonge MJ, Homji N, Mills D, Bendell JC (2014) Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs. doi:10.1007/s10637-014-0082-9

    Google Scholar 

  • Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Parsons R (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65(7):2554–2559. doi:10.1158/0008-5472-can-04-3913

    CAS  PubMed  Google Scholar 

  • Sampath D, Malik A, Plunkett W, Nowak B, Williams B, Burton M, Lancet JE (2013) Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies. Leuk Res 37:1461–1467. doi:10.1016/j.leukres.2013.07.034

    PubMed Central  CAS  PubMed  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554. doi:10.1126/science.1096502

    CAS  PubMed  Google Scholar 

  • Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22(14):2954–2963

    CAS  PubMed  Google Scholar 

  • Santarpia L, El-Naggar AK, Cote GJ, Myers JN, Sherman SI (2008) Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J Clin Endocrinol Metab 93(1):278–284. doi:10.1210/jc.2007-1076

    CAS  PubMed  Google Scholar 

  • Saura C, Bendell J, Jerusalem G, Su S, Ru Q, De Buck S, Baselga J (2014) Phase Ib study of Buparlisib plus Trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on Trastuzumab-based therapy. Clin Cancer Res 20(7):1935–1945. doi:10.1158/1078-0432.ccr-13-1070

    CAS  PubMed  Google Scholar 

  • Schreeder M, Figlin R, Stephenson J, Campos L, Chawla S, Spigel D, Birch R (2008) Phase I multicenter trial of perifosine in combination with sorafenib for patients with advanced cancers including renal cell carcinoma. J Clin Oncol (Meeting Abstracts) 26:16024

    Google Scholar 

  • Schwartz GK, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, Maki RG (2013) Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 14(4):371–382. doi:10.1016/s1470-2045(13)70049-4

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Brana I, Edelman G (2014) Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 20(1):233–245. doi:10.1158/1078-0432.ccr-13-1777

    CAS  PubMed  Google Scholar 

  • Shen L, Chen XD, Zhang YH (2014) MicroRNA-128 promotes proliferation in osteosarcoma cells by downregulating PTEN. Tumour Biol 35(3):2069–2074. doi:10.1007/s13277-013-1274-1

    CAS  PubMed  Google Scholar 

  • Shi Y, Wang J, Chandarlapaty S, Cross J, Thompson C, Rosen N, Jiang X (2014) PTEN is a protein tyrosine phosphatase for IRS1. Nat Struct Mol Biol 21(6):522–527. doi:10.1038/nsmb.2828

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, Patnaik A (2012) The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 18(8):2316–2325. doi:10.1158/1078-0432.ccr-11-2381

    CAS  PubMed  Google Scholar 

  • Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5):283–296. doi:10.1038/nrm3330

    CAS  PubMed  Google Scholar 

  • Stankovic T, Milinkovic V, Bankovic J, Dinic J, Tanic N, Dramicanin T, Tanic N (2014) Comparative analyses of individual and multiple alterations of p53, PTEN and p16 in non-small cell lung carcinoma, glioma and breast carcinoma samples. Biomed Pharmacother. doi:10.1016/j.biopha.2014.03.014

    PubMed  Google Scholar 

  • Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Hennessy BT (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68(15):6084–6091. doi:10.1158/0008-5472.can-07-6854

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sun JM, Kim JR, Do IG, Lee SY, Lee J, Choi YL, Park K (2013) A phase-1b study of everolimus plus paclitaxel in patients with small-cell lung cancer. Br J Cancer 109(6):1482–1487. doi:10.1038/bjc.2013.467

    PubMed Central  CAS  PubMed  Google Scholar 

  • Templeton AJ, Dutoit V, Cathomas R, Rothermundt C, Bärtschi D, Dröge C, Gillessen S (2013) Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol 64(1):150–158. doi:10.1016/j.eururo.2013.03.040

    CAS  PubMed  Google Scholar 

  • Thornton KA, Chen AR, Trucco MM, Shah P, Wilky BA, Gul N, Carrera-Haro MA, Ferreira MF, Shafique U, Powell JD, Meyer CF, Loeb DM (2013) A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma. Int J Cancer 133(4):997–1005. doi:10.1002/ijc.28083

    CAS  PubMed  Google Scholar 

  • Tian L, Fang YX, Xue JL, Chen JZ (2013) Four microRNAs promote prostate cell proliferation with regulation of PTEN and its downstream signals in vitro. PLoS ONE 8(9):75885. doi:10.1371/journal.pone.0075885

    Google Scholar 

  • Tinker AV, Ellard S, Welch S, Moens F, Allo G, Tsao MS, MacKay H (2013) Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. Gynecol Oncol 130(2):269–274. doi:10.1016/j.ygyno.2013.05.008

    CAS  PubMed  Google Scholar 

  • Trinquand A, Tanguy-Schmidt A, Abdelali RB, Lambert J, Beldjord K, Lengliné E, Mossafa H (2013) Toward a NOTCH1/FBXW7/RAS/PTEN–based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a group for research in Adult Acute Lymphoblastic Leukemia Study. J Clin Oncol 31(34):4333–4342

    CAS  PubMed  Google Scholar 

  • Vink SR, Schellens JH, Beijnen JH, Sindermann H, Engel J, Dubbelman R, Verheij M (2006) Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours. Radiother Oncol 80(2):207–213. doi:10.1002/rao.285414

    CAS  PubMed  Google Scholar 

  • Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501

    CAS  PubMed  Google Scholar 

  • Wade M, Li YC, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13(2):83–96. doi:10.1038/nrc3430

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wagner AJ, Bendell JC, Dolly S, Morgan JA, Ware JA, Fredrickson J, Mazina KE, Lauchle JO, Burris HA, De Bono JS (2011) A first-in-human phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors. J Clin Oncol (Meeting Abstracts) 29:3020

    Google Scholar 

  • Wang L, Wang WL, Zhang Y, Guo SP, Zhang J, Li QL (2007a) Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma. Hepatol Res 37(5):389–396. doi:10.1111/j.1872-034X.2007.00042.x

    CAS  PubMed  Google Scholar 

  • Wang Y, Hou P, Yu H, Wang W, Ji M, Zhao S, Xing M (2007b) High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors. J Clin Endocrinol Metab 92(6):2387–2390. doi:10.1210/jc.2006-2019

    CAS  PubMed  Google Scholar 

  • Wang X, Zhan Y, Zhao L, Alvarez J, Chaudhary I, Zhou BB, Feuerstein GZ (2011) Multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor, temsirolimus, in a preclinical mammary carcinoma OncoMouse model: a translational medicine study in support for early clinical development. J Pharmacol Exp Ther 339(2):421–429. doi:10.1124/jpet.111.185249

    CAS  PubMed  Google Scholar 

  • Wang HW, Yang SH, Huang GD, Lin JK, Chen WS, Jiang JK, Teng HW (2014a) Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism. J Cancer Res Clin Oncol 140(4):561–571. doi:10.1007/s00432-014-1596-4

    CAS  PubMed  Google Scholar 

  • Wang Y, Tang Q, Li M, Jiang S, Wang X (2014b) MicroRNA-375 inhibits colorectal cancer growth by targeting PIK3CA. Biochem Biophys Res Commun 444(2):199–204. doi:10.1016/j.bbrc.2014.01.028

    CAS  PubMed  Google Scholar 

  • Waqar SN, Robinson C, Bradley J, Goodgame B, Rooney M, Williams K, Govindan R (2014) A phase I study of temsirolimus and thoracic radiation in non-small-cell lung cancer. Clin Lung Cancer 15(2):119–123. doi:10.1016/j.cllc.2013.11.007

    PubMed Central  PubMed  Google Scholar 

  • Wen PY, Chang SM, Lamborn KR, Kuhn JG, Norden AD, Cloughesy TF, Ligon KL (2014) Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. Neuro Oncol 16(4):567–578. doi:10.1093/neuonc

    CAS  PubMed  Google Scholar 

  • Werner D, Atmaca A, Pauligk C, Pustowka A, Jager E, Al-Batran SE (2013) Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma. Cancer Med 2(3):325–333. doi:10.1002/cam4.77

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, Hayes DF (2013) 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 31(2):195–202. doi:10.1200/jco.2011.38.3331

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wollina U (2012) Cutaneous T cell lymphoma: update on treatment. Int J Dermatol 51(9):1019–1036. doi:10.1111/j.1365-4632.2011.05337

    PubMed  Google Scholar 

  • Wolpin BM, Ng K, Zhu AX, Abrams T, Enzinger PC, McCleary NJ, Fuchs CS (2013) Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer. Oncologist 18(4):377–378. doi:10.1634/theoncologist.2012-0378

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wong KK, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genetics Dev 20(1):87–90. doi:10.1016/j.gde.2009.11.002

  • Wu W, Yang J, Feng X, Wang H, Ye S, Yang P, Zhou Y (2013) MicroRNA-32 (miR-32) regulates phosphatase and tensin homologue (PTEN) expression and promotes growth, migration, and invasion in colorectal carcinoma cells. Mol Cancer 12(1):30

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wunderle L, Badura S, Lang F, Wolf A, Schleyer E, Serve H, Ottmann OG (2013) Safety and efficacy Of BEZ235, a dual PI3-Kinase/mTOR inhibitor, in adult patients with relapsed or refractory acute leukemia: results of a Phase I Study. Blood 122(21):2675

    Google Scholar 

  • Xu WT, Yang Z, Lu NH (2014a) Roles of PTEN (phosphatase and tensin homolog) in gastric cancer development and progression. Asian Pac J Cancer Prev 15(1):17–24

    PubMed  Google Scholar 

  • Xu J, Li Z, Wang J, Chen H, Fang JY (2014b) Combined PTEN mutation and protein expression associate with overall and disease-free survival of glioblastoma patients. Transl Oncol 7(2):196–205. doi:10.1016/j.tranon.2014.02.004

    PubMed Central  PubMed  Google Scholar 

  • Yamamoto H, Shigematsu H, Nomura M, Lockwood WW, Sato M, Okumura N, Gazdar AF (2008) PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 68(17):6913–6921. doi:10.1158/0008-5472.can-07-5084

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang J, Ren Y, Wang L, Li B, Chen Y, Zhao W, Xu W, Li T, Dai F (2010) PTEN mutation spectrum in breast cancers and breast hyperplasia. J Cancer Res Clin Oncol 136(9):1303–1311

    CAS  PubMed  Google Scholar 

  • Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Tolcher AW (2011) First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29(35):4688–4695. doi:10.1200/jco.2011.35.5263

    CAS  PubMed  Google Scholar 

  • Yin L, Liu CX, Nong WX, Chen YZ, Qi Y, Li HA, Li F (2012) Mutational analysis of p53 and PTEN in soft tissue sarcoma. Mol Med Rep 5(2):457–461. doi:10.3892/mmr.2011.660

    CAS  PubMed  Google Scholar 

  • Yin L, Cai W, Liu CX, Chen YZ, Hu JM, Jiang JF, Zhang WJ (2013) Analysis of PTEN methylation patterns in soft tissue Sarcomas by massARRAY spectrometry. PLoS ONE 8(5):62971

    Google Scholar 

  • Zhao L, Teng B, Wen L, Feng Q, Wang H, Li N, Liang Z (2014) mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma. Int J Clin Exp Med 7(2):337–347

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Lim, H.J., Crowe, P. & Yang, JL. Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. J Cancer Res Clin Oncol 141, 671–689 (2015). https://doi.org/10.1007/s00432-014-1803-3

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