**Author details**

Isabella S. Guimarães1,2, Nayara G. Tessarollo1,2, Paulo C.M. Lyra-Júnior1,2, Diandra Z. dos Santos1,3, Roger C. Zampier1 , Laura F.R.L. de Oliveira1 , Krislayne V. Siqueira1 , Ian V. Silva2,4 and Leticia B.A. Rangel1,2,3\*

\*Address all correspondence to: lbarangel@yahoo.com

1 Laboratory of Cellular and Molecular Biology of Human Cancer, Department of Pharmaceutical Sciences, Federal University of Espirito Santo State, Brazil

2 Biotechnology Program, Federal University of Espirito Santo State, Brazil

3 Biochemistry and Pharmacology Program, Federal University of Espirito Santo State, Brazil

4 Department of Morphology, Health Sciences Center, Federal University of Espirito Santo State, Brazil

## **References**


[7] Vadas O., Burke J. E., Zhang X., Berndt A., Williams R. L. Structural basis for activa‐ tion and inhibition of class I phosphoinositide 3-kinases. Science Signaling. 2011;4 (195):re2. DOI: 10.1126/scisignal.2002165

**Author details**

146 Updates on Cancer Treatment

Brazil

State, Brazil

**References**

Diandra Z. dos Santos1,3, Roger C. Zampier1

DOI: 10.1016/j.hoc.2012.02.014

10.1517/14728222.2011.644788

DOI: 10.1038/nature12634

\*Address all correspondence to: lbarangel@yahoo.com

Ian V. Silva2,4 and Leticia B.A. Rangel1,2,3\*

Isabella S. Guimarães1,2, Nayara G. Tessarollo1,2, Paulo C.M. Lyra-Júnior1,2,

Pharmaceutical Sciences, Federal University of Espirito Santo State, Brazil

2 Biotechnology Program, Federal University of Espirito Santo State, Brazil

Oncogene. 2008;27:5497–5510. DOI: 10.1038/onc.2008.245

2014;15(10):18856-91. DOI: 10.3390/ijms151018856

ogy. 2010a;11 (5):329-341. DOI: 10.1038/nrm2882

1 Laboratory of Cellular and Molecular Biology of Human Cancer, Department of

3 Biochemistry and Pharmacology Program, Federal University of Espirito Santo State,

4 Department of Morphology, Health Sciences Center, Federal University of Espirito Santo

[1] Gomez-Pinillos A., Ferrari A.C. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematology/Oncology Clinics of North America. 2012;26(3):483-505.

[2] Yuan T.L., Cantley L.C. PI3K pathway alterations in cancer: variations on a theme.

[3] Li T., Wang G. Computer-aided targeting of the PI3K/Akt/mTOR pathway: toxicity reduction and therapeutic opportunities. International Journal of Molecular Sciences.

[4] Bartholomeusz C., Gonzalez-Angulo, A.M. Targeting the PI3K signaling pathway in cancer therapy. Expert Opinion on Therapeutic Targets. 2012;16(1):121-30. DOI:

[5] Kandoth C., McLellan M.D., Vandin F., Ye K., Niu B., Lu C., et al. Mutational land‐ scape and significance across 12 major cancer types. Nature. 2013;502(7471):333-339.

[6] Vanhaesebroeck B., Guillermet-Guibert J., Graupera M., Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nature Reviews Molecular Cell Biol‐

, Laura F.R.L. de Oliveira1

, Krislayne V. Siqueira1

,


[31] Jacinto E., Loewith R., Schmidt A., Lin S., Ruegg M.A., Hall A., et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biology. 2004;6:1122–1128. DOI: 10.1038/ncb1183

[18] Harlan J.E., Hajduk P.J., Yoon H.S., Fesik S.W. Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate. Nature. 1994;371(6493):168–170. DOI:

[19] Cheever M.L., Sato T.K., de Beer T., Kutateladze T.G, Emr S.D., Overduin M. Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole mem‐

[20] Ellson C.D., Gobert-Gosse S., Anderson K.E., Davidson K, Erdjument-Bromage H., Tempst P., et al. PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox). Nature Cell Biology. 2001;3(7):679-682. DOI:

[21] Kanai F., Liu H., Field S.J., Akbary H., Matsuo T., Brown G.E., et al. The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nature Cell Biology.

[22] Song X., Xu W., Zhang A., Huang G., Liang X., Virbasius J.V., et al. Phox homology domains specifically bind phosphatidylinositol phosphates. Biochemistry.

[23] Xu Y., Hortsman H., Seet L., Wong S.H., Hong W. SNX3 regulates endosomal func‐ tion through its PXdomain-mediated interaction with PtdIns(3)P. Nature Cell Biolo‐

[24] Sarbassov D.D., Ali S.M., Sengupta S., Sheen J.H., Hsu P.P., Bagley A.F., et al. Pro‐ longed rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular

[25] Petrulea M.S., Plantinga T.S., Smit J.W., Georgescu C.E., Netea-Maier R.T. PI3K/Akt/ mTOR: a promising therapeutic target for non-medullary thyroid carcinoma. Cancer

[26] Mukohara T. PI3K mutations in breast cancer: prognostic and therapeutic implica‐ tions. Breast Cancer (Dove Medical Press). 2015;7:111-23. DOI: 10.2147/BCTT.S60696

[27] Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes & Development.

[28] Larue L., Bellacosa A. Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene. 2005;24(50):

[29] Manning B.D., Cantley L.C. Rheb fills a GAP between TSC and TOR. Trends of Bio‐ chemical Sciences. 2003;28(11):573-6. DOI: http://dx.doi.org/10.1016/j.tibs.2003.09.003

[30] Engelman J.A., Luo J., Cantley L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Reviews Genetics. 2006;7(8):606-19.

Cell. 2006;22(2):159-168. DOI: http://dx.doi.org/10.1016/j.molcel.2006.03.029

Treatment Reviews. 2015;26. DOI: 10.1016/j.ctrv.2015.06.005

branes. Nature Cell Biology. 2001;3(7):613–8. DOI: 10.1038/35083000

10.1038/371168a0

148 Updates on Cancer Treatment

10.1038/35083076

2001;3(7):675-678. DOI: 10.1038/35083070

2001;40(30):8940-8944. DOI: 10.1021/bi0155100

gy. 2001;3(7):658-666. DOI: 10.1038/35083051

2004;18(16):1926-45. DOI: 10.1101/gad.1212704

7443-7454. DOI: 10.1038/sj.onc.1209091

DOI: 10.1038/nrg1879


[53] Rodon J., Dienstmann R., Serra V., Tabemero J. Development of PI3K inhibitors: les‐ sons learned from early clinical trials. Nature Reviews. Clinical Oncology. 2013;10(3): 143–153. DOI: 10.1038/nrclinonc.2013.10

[43] Kuo K.T, Mao T. L., Jones S., Veras E., Ayhan A., Wang T.L., et al. Frequent activat‐ ing mutations of PIK3CA in ovarian clear cell carcinoma. American Journal of Path‐

[44] Kinross K.M., Montgomery K.G., Kleinschmidt M., Waring P., Ivetac I., Tikoo A. et al. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovari‐ an tumorigenesis in mice. Journal of Clinical Investigation. 2012;122(2):553-557. DOI:

[45] Tanwar P.S., Zhang L., Kaneko-Tarui T., Curley M.D., Taketo M.M., Rani P. Mamma‐ lian target of rapamycin is a therapeutic target for murine ovarian endometrioid ade‐ nocarcinomas with dysregulated Wnt/β-catenin and PTEN. PLoS One.

[46] Steuer-Vogt M.K., Bonkowsky V., Ambrosch P., Scholz M., Neiss A., Strutz J., et al. The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. European Journal of Cancer.

[47] Dancey J.E. Clinical development of mammalian target of rapamycin inhibitors. Hematology Oncology Clinics North of American. 2002;16(5):1101-14. PII:

[48] Huang S., Houghton P.J. Inhibitors of mammalian target of rapamycin as novel anti‐ tumor agents: from bench to clinic. Current Opinion in Investigational Drugs.

[49] Wander S.A, Hennessy B.T, Slingerland J.M. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. Journal of

[50] Mabuchi S., Kawase C., Altomare D.A., Morishige K., Sawada K., Hayashi M., et al. mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-re‐ sistant clear cell carcinoma of the ovary. Clinical Cancer Research. 2009;15 (17):

[51] Peng C.L., Lai P.S., Lin F.H., Yueh-Hsiu W.S., Shieh M.J. Dual chemotherapy and photodynamic therapy in an HT-29 human colon cancer xenograft model using SN-38-loaded chlorin-core star block copolymer micelles. Biomaterial. 2009;30:3614–

[52] Zhang, P.; Hu, L.; Yin, Q.; Zhang, Z.; Feng, L.; Li, Y. Transferrin-conjugated poly‐ phosphoester hybrid micelle loading paclitaxel for brain-targeting delivery: synthe‐ sis, preparation and in vivo evaluation. Journal of Controlled Release 2012;159:429–

Clinical Investigation. 2011;121(4):1231-1241. DOI: 10.1172/JCI44145

ology. 2009;174(5): 1597–1601. DOI: 10.2353/ajpath.2009.081000

2011;6(6):e20715. DOI: 10.1371/journal.pone.0020715

2001;37(1):23-31. DOI: 10.1016/S0959-8049(00)00360-9

10.1172/JCI59309

150 Updates on Cancer Treatment

S0889-8588(02)00051-5

2002;3(2):295-304. PMID: 12020063

5404-5413. DOI: 10.1158/1078-0432.CCR-09-0365

3625. DOI: 10.1016/j.biomaterials.2009.03.048

434. DOI: 10.1016/j.jconrel.2012.01.031


[75] Folkes A., Ahmadi K., Alderton W.K., Alix S., Baker S.J., Box G. et al. The identifica‐ tion of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpho‐ lin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. Journal Medici‐ nal Chemistry. 2008;51(18):5522-5532. DOI: 10.1021/jm800295d

[65] Burger M., Pecchi S., Wagman A., Ni Z.J., Knapp M., Hendrickson T., et al. Identifica‐ tion of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase in‐ hibitor for treating cancer. ACS Medicinal Chemistry Letters. 2011;2(10):774-779.

[66] Maira S.M., Pecchi S., Huang A., Burger M., Knapp M., Sterker D., et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase in‐ hibitor. Molecular Cancer Therapeutics. 2012;11(2):317-328. DOI:

[67] Bendell J.C., Rodon J., Burris H.A., 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. Journal of Clinical Oncology. 2012;30(3):282-290. DOI:

[68] Rodon J., Braña I., Siu L.L., De Jonge M.J., Homji N., Mills D., et al. Phase I dose-esca‐ lation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibi‐ tor, in patients with advanced solid tumors. Investigational New Drugs. 2014;32(4):

[69] Edelman G., Bedell C., Shapiro G., Pandya S.S., Kwak E.L., Scheffold C., et al. A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies. Journal of Clinical Oncology.

[70] Markman B., Dienstmann R., Tabernero J. Targeting the PI3K/Akt/mTOR pathway—

[71] Foster P., Yamaguchi K., Hsu PP., Qian F., Du X., Wu J., et al. The selective PI3K in‐ hibitor XL147 (SAR245408) inhibits tumor growth and survival and potentiates the activity of chemotherapeutic agents in preclinical tumor models. Molecular Cancer

[72] Shapiro G.I., Rodon J., Bedell C., Kwak EL., Baselga J., Braña I., et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral panclass I PI3K inhibitor, in patients with advanced solid tumors. Clinical Cancer Re‐

[73] Soria J.C., LoRusso P., Bahleda R., Lager J., Liu L., Jiang J., et al. Phase I dose-escala‐ tion study of pilaralisib (SAR245408, XL147), a pan-Class I PI3K inhibitor, in combi‐ nation with erlotinib in patients with solid tumors. Oncologist. 2015;20(3):245-6. DOI:

[74] Tolaney S., Burris H., Gartner E., Mayer I.A., Saura C., Maurer M., et al. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Research Treatment. 2015;149(1):151-161. DOI: 10.1007/

Therapeutics. 2015;14(4):931-940. DOI: 10.1158/1535-7163.MCT-14-0833

beyond rapalogs. Oncotarget. 2010;1(7):530-543. PMC3248125

search. 2014;20(1):233-45. DOI: 10.1158/1078-0432.CCR-13-1777

DOI: 10.1021/ml200156t

152 Updates on Cancer Treatment

10.1200/JCO.2011.36.1360

2010;28(15s):3004.

10.1158/1535-7163.MCT-11-0474.

670-81. DOI: 10.1007/s10637-014-0082-9

10.1634/theoncologist.2014-0449

s10549-014-3248-4


[95] Herman S.E., Gordon A.L., Wagner A.J., Heerema N.A., Zhao W., Flynn J.M., et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activ‐ ity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078-2088.

[85] Rommel C., Camps M., Ji H. PI3K delta and PI3K gamma: partners in crime in in‐ flammation in rheumatoid arthritis and beyond? Nature Reviews Immunology.

[86] U.S. Food and Drug Administration. U.S. Department of Health and Human Serv‐ ices. [Internet]. 2015. Available from: http://www.fda.gov/ICECI/Inspections/

[87] Fritsch C., Huang A., Chatenay-Rivauday C., Schnell C., Reddy A., Liu M., et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and develop‐ ment of the patient stratification strategy for clinical trials. Molecular Cancer Thera‐

[88] Fritsch C.M., Schnell C., Chatenay-Rivauday C., Guthy D.A., de Pover A., Wartmann M., et al. NVP-BYL719, a novel PI3Kalpha selective inhibitor with all the characteris‐ tics required for clinical development as an anti-cancer agent. Cancer Research.

[89] Huang A., Fritsch C., Wilson C., et al. Single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel. Cancer Research. 2012;3749. DOI:

[90] Gonzalez-Angulo A.M., Juric D., Argiles G., Schellens J.H., Burris H.A, Berlin J., et al. Safety, pharmacokinetics, and preliminary activity of the {alpha}-specific PI3K inhibi‐ tor BYL719: results from the first-in-human study. Journal of Clinical Oncology.

[91] Ndubaku C.O., Heffron T.P., Staben S.T., Baumgardner M., Blaquiere N., Bradley E., et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6 dihydro‐ benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2 methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound ex‐ posure and robust in vivo antitumor activity. Journal of Medicinal Chemistry.

[92] Wallin J.J., Edgar K.A., Guan J., Sampath D., Nannini M., Belvin M., et al. Abstract P2-17-01: the PI3K inhibitor GDC-0032 is selectively potent against PIK3CA mutant breast cancer cell lines and tumors. Cancer Research. 2013;73:P2-17-01. DOI:

[93] Juric D., Krop I., Ramanathan R.K., Xiao J., Sanabria S., Wilson T.R., et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human phase Ia dose esca‐ lation study. In: AACR 104th Annual Meeting 2013; April 2013; Washington, DC;

[94] Yang Q., Modi P., Newcomb T., Qu C., Gandhi V. Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leu‐ kemia, and follicular lymphoma. Clinical Cancer Research. 2015;21(7):1537-1542.

peutics. 2014;13(5):1117-29. DOI: 10.1158/1535-7163.MCT-13-0865

2007;7(3):191-201. DOI: 10.1038/nri2036

154 Updates on Cancer Treatment

ucm250729.htm [Accessed: 2015-03-11]

2012;3748. DOI: 10.1158/1538-7445.AM2012-3748

2013;56(11):4597-4610. DOI: 10.1021/jm4003632

10.1158/0008-5472.SABCS13-P2-17-01

DOI: 10.1158/1078-0432.CCR-14-2034

10.1158/1538-7445.AM2012-3749

2013;31:Abstract: 2531

73:LB–64.


in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107(10):4053-4062. DOI: http://dx.doi.org/10.1182/blood-2005-08-3434


[116] Guertin D.A., Sabatini D.M. The pharmacology of mTOR inhibition. Science Signal‐ ling. 2009;2(67):pe24. DOI: 10.1126/scisignal.267pe24

in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107(10):4053-4062.

[106] Xin Y., Shen X.D., Cheng L., Hong D.F., Chen B. Perifosine inhibits S6K1-Gli1 signal‐ ing and enhances gemcitabine-induced anti-pancreatic cancer efficiency. Cancer Che‐ motherapy and Pharmacology. 2014;73(4):711-719. DOI: 10.1007/s00280-014-2397-9

[107] Posadas E.M, Gulley J., Arlen P.M., Trout A., Parnes H.L., Wright J., et al. A phase II study of perifosine in androgen independent prostate cancer. Cancer Biology Thera‐

[108] Argiris A., Cohen E., Karrison T., Esparaz B., Mauer A., Ansari R., et al. Phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biology and Therapy. 2006;5(7):766-770. DOI: 10.4161/cbt.5.7.2874

[109] Knowling M., Blackstein M., Tozer R., Bramwell V., Dancey J., Dore N., et al. A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: a National Cancer Institute of Canada Clinical Trials Group trial. Investigational New Drugs. 2006;24(5):435-439. DOI: 10.1007/

[110] Marsh Rde W., Rocha Lima C.M., Levy D.E., Mitchell E.P., Rowland Jr K.M., Benson A.B. A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma. American Journal of Clinical Oncology. 2007;30(1):26–31.

[111] Leighl N.B., Dent S., Clemons M., Vandenberg T.A., Tozer R., Warr D.G., et al. A phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer

[112] Fu S., Hennessy B.T., Ng C.S., Ju Z., Coombes K.R., Wolf J.K., et al. Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epi‐ thelial ovarian cancer. Gynecologic Oncology. 2012;126(1):47-53. DOI: 10.1016/

[113] Guidetti A., Carlo-Stella C., Locatelli SL., Malorni W., Mortarini R., Viviani S., et al. Phase II study of perifosine and sorafenib dual-targeted therapy in patients with re‐ lapsed or refractory lymphoproliferative diseases. Clinical Cancer Research.

[114] Rhodes N., Heerding D.A., Duckett D.R., Eberwein D.J., Knick V.B., Lansing T.J., et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Research. 2008;68(7):2366-74. DOI:

[115] Feng Z., Zhang H., Levine A. J., Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. PNAS, Proceedings of the National Academy of Sciences.

Research Treatment. 2008;108(1):87-92. DOI: 10.1007/s10549-007-9584-x

2014;20(22):5641-5651. DOI: 10.1158/1078-0432.CCR-14-0770

2005;102(23): 8204–8209. DOI: 10.1073/pnas.0502857102

DOI: http://dx.doi.org/10.1182/blood-2005-08-3434

py. 2005;4(10):1133-1137. DOI: 10.4161/cbt.4.10.2064

DOI: 10.1097/01.coc.0000251235.46149.43

s10637-006-6406-7

156 Updates on Cancer Treatment

j.ygyno.2012.04.006

10.1158/0008-5472.CAN-07-5783


[138] Bae-Jump V.L., Zhou C., Boggess J.F., Gehring P.A. Synergistic effect of rapamycin and cisplatin in endometrial cancer cells. Cancer. 2009;115:3887:96. DOI: 10.1002/cncr. 24431

[127] Zaytseva Y.Y., Valentino J.D., Gulhati P., Evers B.M. mTOR inhibitors in cancer ther‐

[128] Brown E.J., Albers M.W., Shin T.B., Ichikawa K., Keith C.T., Lane W.S., et al. A mam‐ malian protein targeted by G1-arresting rapamycin-receptor complex. Nature.

[129] Sabatini D.M., Erdjument-Bromage H., Lui M., Tempst P., Snyder S.H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. 1994;78(1):35-43. DOI: http://dx.doi.org/

[130] Vignot S., Faivre S., Aguirre D., Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Annals of Oncology. 2005;16(4):524-37. DOI: 10.1093/annonc/

[131] Duran I., Siu L.L., Oza A.M., Chung T.B., Sturgeon J., Townsley C.A., et al. Charac‐ terisation of the lung toxicity of the cell cycle inhibitor temsirolimus. European Jour‐ nal of Cancer. 2006;42(12):1875-1880. DOI: http://dx.doi.org/10.1016/j.ejca.2006.03.015

[132] National Cancer Institute [Internet]. 2013. Available from: http://www.cancer.gov/

[133] Pavel M.E., Hainsworth J.D., Baudin E., Peeters M., Horsch D., Winkler R.E., et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neu‐ roendocrine tumours associated with carcinoid syndrome (RADIANT-2): a rando‐ mised, placebo-controlled, phase 3 study. Lancet. 2011;378(9808):2005-2012. DOI:

[134] Burris H.A., Lebrun F., Rugo H.S., Beck J.T, Piccart M., Neven P., et al. Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exmestane versus placebo plus exemestane in the phase 3, randomized, controlled,

[135] André F., O'Regan R., Ozguroglu M., Toi M., Xu B., Jerusalem G., et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BO‐ LERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol‐

[136] Hurvitz S.A., Dalenc F., Campone M., O'Regan R.M., Tjan-Heijnen V.C., Gligorov J., et al. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Research and Treatment.

[137] Huang S., Houghton P.J. Targeting mTOR signaling for cancer therapy. Current Opinion of Pharmacology 2003;3:371–7. DOI: 10.1016/S1471-4892(03)00071-7

BOLERO-2 trial. Cancer. 2013;119(10):1908-1915. DOI: 10.1002/cncr.28010

ogy. 2014;15(6):580-91. DOI: 10.1016/S1470-2045(14)70138-X

2013;141(3): 437-446. DOI: 10.1007/s10549-013-2689-5

about-cancer/treatment/drugs/fda-everolimus. [Accessed: 2015-05-20].

apy. Cancer Letters. 2012;319(1):1-7. DOI: 10.1016/j.canlet.2012.01.005

1994;369(6483):756-758. DOI: 10.1038/369756a0

10.1016/0092-8674(94)90570-3

10.1016/S0140-6736(11)61742-X

mdi113


[160] Rodrik-Outmezguine V., Chandarlapaty S., Pagano N., Poulikakos P.I., Scaltriti M., Moskatel E., et al. mTOR kinase inhibition causes feedback-dependent biphasic regu‐ lation of AKT signaling. Cancer Discovery. 2011;3:248-259. DOI: doi: 10.1158/2159-8290.CD-11-0085

[150] Yu K., Toral-Barza L., Shi C., Zhang W.G., Lucas J., Shor B., et al. Biochemical, cellu‐ lar, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Research. 2009;69(15):6232-6240. DOI:

[151] Chresta C.M., Davies B.R., Hickson I., Harding T., Cosulich S., Critchlow S.E., et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.

[152] Yu K., Shi C., Toral-Barza L., Lucas J., Shor B., Kim J.E., et al. Beyond rapalog thera‐ py. Preclinical pharmacology and antitumor activity of WYE-125132, an ATP-com‐ petitive and -specific inhibitor of mTORC1 and mTORC2. Cancer Research.

[153] Bhagwat V.S., Gokhale P.C., Crew A.P., Cooke A., Yao Y., Mantis C., et al. Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Molecular Cancer Therapeutics. 2011;10(8):

[154] Thoreen C.C., Kang S.A, Chang J.W., Liu Q., Zhang J., Gao Y., et al. An ATP-competi‐ tive mammalian target of rapamycin inhibitor reveals rapamycin-insensitive func‐ tions of mTORC1. Journal of Biological Chemistry. 2009;284(12):8023-8032. DOI:

[155] Zhang H., Berel D., Wang Y., Li P., Bhowmick N.A., Figlin R.A., et al. A comparison of Ku0063794, a dual mTORC1 and mTORC2 inhibitor, and temsirolimus in preclini‐ cal renal cell carcinoma models. PLoS One. 2013;8(1):e54918. DOI: 10.1371/jour‐

[156] Blaser B., Waselle L., Dormond-Meuwly A., Dufour M., Roulin D., Demartines N., et al. Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer

[157] Liu Q., Wang J., Kang S.A., Thoreen C.C., Hur W., Ahmed T., et al. Discovery of 9-(6 aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H) one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. Journal of Medicinal Chemistry.

[158] Patricelli MP, Nomanbhoy TK, Wu J, Brown H, Zhou D, Zhang J, et al. In situ kinase profiling reveals functionally relevant properties of native kinases. Chemistry and Bi‐

[159] Liu Q., Xu C., Kirubakaran S., Zhang X., Hur W. Liu Y., et al. Characterization of Tor‐ in2, an ATP-competitive inhibitor of mTOR, ATM and ATR. Cancer Research. 2013;

cells.BMC Cancer. 2012;12:86. DOI: 10.1186/1471-2407-12-86

ology. 2011;18(6):699-710. DOI: 10.1016/j.chembiol.2011.04.011

2011;54(5):1473-80. DOI: 10.1021/jm101520v

73(8):2574-86. DOI: 10.1158/0008-5472

Cancer Research. 2010;70(1):288-298. DOI: 10.1158/0008-5472.CAN-09-1751

2010;70(2):621-631. DOI: 10.1158/0008-5472.CAN-09-2340

1394-1406. DOI: 10.1158/1535-7163.MCT-10-1099

10.1074/jbc.M900301200

nal.pone.0054918

10.1158/0008-5472.CAN-09-0299


[180] McMillin D.W., Ooi M., Delmore J., Negri J., Hayden P., Mitsiades N., et al. Antimye‐ loma activity of the orally bioavailable dual phosphatidylinositol 3- kinase/mammali‐ an target of rapamycin inhibitor NVP-BEZ235. Cancer Research. 2009;69(14): 5835-5842. DOI: 10.1158/0008-5472.CAN-08-4285

[170] Papadopoulos K.P., Tabernero J., Markman B., Patnaik A., Tolcher A.W., Baselga J., et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with ad‐ vanced solid tumors. Clinical Cancer Research. 2014;20(9):2445-56. DOI:

[171] Courtney K.D., Corcoran R.B., Engelman J.A. The PI3K pathway as drug target in hu‐ man cancer. Journal of Clinical Oncology. 2010;28(6):1075-1083. DOI: 10.1200/JCO.

[172] O'Reilly K.E., Rojo F., She Q.B., Solit D., Mills G.B., Smith D., et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Re‐

[173] Liu T.J., Koul D., LaFortune T., Tiao N., Shen R.J., Maira S.M., et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Molecular Cancer Thera‐

[174] Santiskulvong C., Konecny G.E., Fekete M., Chen K.Y., Karam A., Mulholland D., et al. Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clinical Cancer Research. 2011;17(8):2373–2384. DOI: 10.1158/1078-0432.CCR-10-2289

[175] Sanchez C.G., Ma C.X., Crowder R.J., Guintoli T., Phommaly C., Gao F., et al. Preclin‐ ical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Research.

[176] O'Brien N.A., McDonald K., Tong L., von Euw E., Kalous O., Conklin D., et al. Tar‐ geting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT. Clinical Cancer Research. 2014;20(13):3507-3520. DOI:

[177] Schnell C.R., Stauffer F., Allegrini P.R., O'Reilly T., McSheehy P.M., Dartois C., et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin in‐ hibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging.

Cancer Research. 2008;68(16):6598–6607. DOI: 10.1158/0008-5472.CAN-08-1044 [178] Cao P., Maira S.M., Garcia-Echeverria C., Hedley D.W. Activity of a novel, dual PI3 kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. British Journal of Cancer. 2009;100(8):1267–1276.

[179] Marone R., Erhart D., Mertz A.C., Bohnacker T., Schnell C., Cmiljanovic V., et al. Tar‐ geting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamy‐ cin inhibitors. Molecular Cancer Research. 2009;7(4):601–613. DOI:

search. 2006;66(3):1500- 1508. DOI: 10.1158/0008-5472.CAN-05-2925

py. 2009;8(8):2204–2210. DOI: 10.1158/1535-7163

2011;13(2):1-17. DOI: 10.1186/bcr2833

10.1158/1078-0432.CCR-13-2769

DOI: 10.1038/sj.bjc.6604995

10.1158/1541-7786.MCR-08-0366

10.1158/1078-0432.CCR-13-2403

2009.25.3641

