PI3K and Akt as molecular targets for cancer therapy: Current clinical outcomes

Acta Pharmacologica Sinica

Volumn 33, Issue 12, 2012, Pages 1441-1458

  Pal, Ipsita ^a   Mandal, Mahitosh ^a  

^a INDIAN INSTITUTE OF TECHNOLOGY   (India)

Author keywords

Akt; Anticancer drug; Clinical trials; Kinase inhibitors; PI3K

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; ANTHRACYCLINE DERIVATIVE; BGT 226; BUPARLISIB; DOCETAXEL; DOXORUBICIN; ERLOTINIB; EVEROLIMUS; GDC 0980; GEMCITABINE; MORPHOLINE DERIVATIVE; PERTUZUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PICTILISIB; PKI 402; PKI 587; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; SELUMETINIB; SORAFENIB; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VINCRISTINE; WORTMANNIN; XL 147; XL 765;

ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; BREAST METASTASIS; CANCER CELL; CANCER CONTROL; CANCER GROWTH; CARCINOGENESIS; CELL STRESS; CHEMOTHERAPY INDUCED NAUSEA AND VOMITING; CHILL; DIARRHEA; DRUG EFFICACY; DRUG FEVER; DRUG MECHANISM; DRUG SAFETY; DRUG TARGETING; ENZYME ACTIVATION; ENZYME REGULATION; FATIGUE; FLATULENCE; GENE MUTATION; GLIOBLASTOMA; GLIOMA; HUMAN; HYPERGLYCEMIA; IC 50; IN VITRO STUDY; IN VIVO STUDY; KIDNEY CARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; LYMPHOMA; MELANOMA; MESOTHELIOMA; MOLECULARLY TARGETED THERAPY; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUROBLASTOMA; NEUROENDOCRINE TUMOR; NONHUMAN; OUTCOME ASSESSMENT; OVARY CANCER; PANCREAS ADENOCARCINOMA; PROSTATE CANCER; PROTEIN PHOSPHORYLATION; PRURITUS; RHABDOMYOSARCOMA; SARCOMA; SIGNAL TRANSDUCTION; SOLID TUMOR;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; MOLECULAR STRUCTURE; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASE; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION;

EID: 84870853860     PISSN: 16714083     EISSN: 17457254     Source Type: Journal    
DOI: 10.1038/aps.2012.72     Document Type: Article

References (178)

1. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKTpathway in human cancer. Nat Rev Cancer 2002; 2: 489-501
2. Vanhaesebroeck B, Waterfield MD. Signaling by distinct classes ofphosphoinositide 3-kinases. Exp Cell Res 1999; 253: 239-54
3. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. AnnuRev Biochem 1998; 67: 481-507
4. Jimenez C, Hernandez C, Pimentel B, Carrera AC. The p85 regulatorysubunit controls sequential activation of phosphoinositide 3-kinaseby Tyr kinases and Ras. J Biol Chem 2002; 277: 41556-62
5. Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH,et al. The phosphatidylinositol 3′-kinase p85alpha gene is an oncogenein human ovarian and colon tumors. Cancer Res 2001; 61:7426-9
6. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296: 1655-7
7. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB,et al. Characterization of a 3-phosphoinositide-dependent proteinkinase which phosphorylates and activates protein kinase Balpha.Curr Biol 1997; 7: 261-9
8. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. CancerTreat Rev 2004; 30: 193-204
9. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signalingnetwork: receptor heterodimerization in development and cancer.EMBO J 2000; 19: 3159-67
10. Siegel PM, Ryan ED, Cardiff RD, Muller WJ. Elevated expressionof activated forms of Neu/ErbB-2 and ErbB-3 are involved in theinduction of mammary tumors in transgenic mice: implications forhuman breast cancer. EMBO J 1999; 18: 2149-64
11. Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites forphosphatidylinositol 3′-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J 1994; 13: 2831-41
12. Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The type1 insulin-like growth factor receptor pathway. Clin Cancer Res 2008;14: 6364-70
13. Belfiore A, Malaguarnera R. Insulin receptor and cancer. EndocrRelat Cancer 2011; 18: R125-47
14. Gallagher EJ, LeRoith D. The proliferating role of insulin and insulinlikegrowth factors in cancer. Trends Endocrinol Metab 2010; 21:610-8
15. Kim SY, Toretsky JA, Scher D, Helman LJ. The role of IGF-1R inpediatric malignancies. Oncologist 2009; 14: 83-91
16. Surmacz E. Growth factor receptors as therapeutic targets: strategiesto inhibit the insulin-like growth factor I receptor. Oncogene 2003;22: 6589-97
17. Wang H, Yin Y, Li W, Zhao X, Yu Y, Zhu J, et al. Over-expression ofPDGFR-beta promotes PDGF-induced proliferation, migration, andangiogenesis of EPCs through PI3K/Akt signaling pathway. PLoS One2012; 7: e30503
18. Heldin CH. Simultaneous induction of stimulatory and inhibitorysignals by PDGF. FEBS Lett 1997; 410: 17-21
19. Heldin CH, Ostman A, Ronnstrand L. Signal transduction via plateletderivedgrowth factor receptors. Biochim Biophys Acta 1998; 1378:F79-113
20. Ferrara N. Vascular endothelial growth factor as a target for anticancertherapy. Oncologist 2004; 9: 2-10
21. Abid MR, Guo S, Minami T, Spokes KC, Ueki K, Skurk C, et al.Vascular endothelial growth factor activates PI3K/Akt/forkheadsignaling in endothelial cells. Arterioscler Thromb Vasc Biol 2004;24: 294-300
22. Kowanetz M, Ferrara N. Vascular endothelial growth factor signalingpathways: therapeutic perspective. Clin Cancer Res 2006; 12:5018-22
23. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, BreitmanML, et al. Failure of blood-island formation and vasculogenesis inFlk-1-deficient mice. Nature 1995; 376: 62-6
24. Takahashi T, Yamaguchi S, Chida K, Shibuya M. A single autophosphorylationsite on KDR/Flk-1 is essential for VEGF-A- dependentactivationof PLC-gamma and DNA synthesis in vascular endothelialcells. EMBO J 2001; 20: 2768-78
25. Holmqvist K, Cross MJ, Rolny C, Hagerkvist R, Rahimi N, MatsumotoT, et al. The adaptor protein shb binds to tyrosine 1175 in vascularendothelialgrowth factor (VEGF) receptor-2 and regulates VEGFdependentcellular migration. J Biol Chem 2004; 279: 22267-75
26. Fujio Y, Walsh K. Akt mediates cytoprotection of endothelial cellsby vascular endothelial growth factor in an anchorage-dependentmanner. J Biol Chem 1999; 274: 16349-54
27. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, et al.Vascular endothelial growth factor regulates endothelial cell survivalthrough the phosphatidylinositol 3′-kinase/Akt signal transductionpathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998;273: 30336-43
28. Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis:the role in receptor desensitization and signaling. PharmacolRev 2001; 53: 1-24
29. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B.The emerging mechanisms of isoform-specific PI3K signalling. NatRev Mol Cell Biol 2010; 11: 329-41
30. Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F,Bilancio A, et al. The p110beta isoform of phosphoinositide 3-kinasesignals downstream of G protein-coupled receptors and is functionallyredundant with p110gamma. Proc Natl Acad Sci USA 2008;105: 8292-7
31. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML,Hooi CS, et al. Mutation of the PIK3CA gene in ovarian and breastcancer. Cancer Res 2004; 64: 7678-81
32. Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in humancancers. Cell Cycle 2004; 3: 1221-4
33. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer.Annu Rev Pathol 2009; 4: 127-50
34. Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutationsidentified in human cancer are oncogenic. Proc Natl Acad Sci USA2005; 102: 802-7
35. Simpson L, Parsons R. PTEN: life as a tumor suppressor. Exp CellRes 2001; 264: 29-41
36. Nicholson KM, Anderson NG. The protein kinase B/Akt signallingpathway in human malignancy. Cell Signal 2002; 14: 381-95
37. Bozulic L, Hemmings BA. PIKKing on PKB: regulation of PKB activityby phosphorylation. Curr Opin Cell Biol 2009; 21: 256-61
38. Huang J, Manning BD. A complex interplay between Akt, TSC2 andthe two mTOR complexes. Biochem Soc Trans 2009; 37: 217-22
39. Hers I, Vincent EE, Tavare JM. Akt signalling in health and disease.Cell Signal 2011; 23: 1515-27
40. Yang WL, Wu CY, Wu J, Lin HK. Regulation of Akt signaling activationby ubiquitination. Cell Cycle 2010; 9: 487-97
41. Konishi H, Matsuzaki H, Tanaka M, Takemura Y, Kuroda S, Ono Y, etal. Activation of protein kinase B (Akt/RAC-protein kinase) by cellularstress and its association with heat shock protein Hsp27. FEBS Lett1997; 410: 493-8
42. van Gorp AG, Pomeranz KM, Birkenkamp KU, Hui RC, Lam EW, CofferPJ. Chronic protein kinase B (PKB/c-akt) activation leads to apoptosisinduced by oxidative stress-mediated Foxo3a transcriptional upregulation.Cancer Res 2006; 66: 10760-9
43. Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA,et al. Molecular alterations of the AKT2 oncogene in ovarian andbreast carcinomas. Int J Cancer 1995; 64: 280-5
44. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK,et al. Amplification of AKT2 in human pancreatic cells and inhibitionof AKT2 expression and tumorigenicity by antisense RNA. Proc NatlAcad Sci USA 1996; 93: 3636-41
45. Ballif BA, Roux PP, Gerber SA, MacKeigan JP, Blenis J, Gygi SP. Quantitativephosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumorsuppressors. Proc Natl Acad Sci USA 2005; 102: 667-72
46. Biggs WH 3rd, Meisenhelder J, Hunter T, Cavenee WK, Arden KC.Protein kinase B/Akt-mediated phosphorylation promotes nuclearexclusion of the winged helix transcription factor FKHR1. Proc NatlAcad Sci USA 1999; 96: 7421-6
47. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Aktpromotes cell survival by phosphorylating and inhibiting a Forkheadtranscription factor. Cell 1999; 96: 857-68
48. Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999; 401: 86-90
49. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NFkappaBactivation by tumour necrosis factor requires the Akt serinethreoninekinase. Nature 1999; 401: 82-5
50. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinaseAkt. Science 1997; 278: 687-9
51. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylationof BAD couples survival signals to the cell-intrinsic deathmachinery. Cell 1997; 91: 231-41
52. Ferkey DM, Kimelman D. GSK-3: new thoughts on an old enzyme.Dev Biol 2000; 225: 471-9
53. Kim L, Kimmel AR. GSK3, a master switch regulating cell-fatespecification and tumorigenesis. Curr Opin Genet Dev 2000; 10:508-14
54. Castaneda CA, Cortes-Funes H, Gomez HL, Ciruelos EM. Thephosphatidyl inositol 3-kinase/AKT signaling pathway in breastcancer. Cancer Metastasis Rev 2010; 29: 751-9
55. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, VanhaesebroeckB, Waterfield MD, et al. Wortmannin inactivates phosphoinositide3-kinase by covalent modification of Lys-802, a residue involved inthe phosphate transfer reaction. Mol Cell Biol 1996; 16: 1722-33
56. Wetzker R, Rommel C. Phosphoinositide 3-kinases as targets fortherapeutic intervention. Curr Pharm Des 2004; 10: 1915-22
57. Semba S, Itoh N, Ito M, Harada M, Yamakawa M. The in vitro and invivo effects of 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), aspecific inhibitor of phosphatidylinositol 3'-kinase, in human coloncancer cells. Clin Cancer Res 2002; 8: 1957-63
58. Fan QW, Specht KM, Zhang C, Goldenberg DD, Shokat KM, WeissWA. Combinatorial efficacy achieved through two-point blockadewithin a signaling pathway-a chemical genetic approach. CancerRes 2003; 63: 8930-8
59. Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor ofphosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4- one (LY294002). J Biol Chem 1994; 269: 5241-8
60. Zhang YJ, Duan Y, Zheng XF. Targeting the mTOR kinase domain: thesecond generation of mTOR inhibitors. Drug Discov Today 2011; 16:325-31
61. Ozbay T, Durden DL, Liu T, O'Regan RM, Nahta R. In vitro evaluationof pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive andtrastuzumab- resistant HER2-over-expressing breast cancer cells.Cancer Chemother Pharmacol 2010; 65: 697-706
62. Peirce SK, Findley HW, Prince C, Dasgupta A, Cooper T, DurdenDL. The PI-3 kinase-Akt-MDM2-survivin signaling axis in high-riskneuroblastoma: a target for PI-3 kinase inhibitor intervention. CancerChemother Pharmacol 2011; 68: 325-35
63. Hayakawa M, Kaizawa H, Moritomo H, Koizumi T, Ohishi T, OkadaM, et al. Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinasep110alpha inhibitors. Bioorg Med Chem 2006; 14: 6847-58
64. Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G,et al. Molecular pharmacology and antitumor activity of PX-866, anovel inhibitor of phosphoinositide-3-kinase signaling. Mol CancerTher 2004; 3: 763-72
65. Koul D, Shen R, Kim YW, Kondo Y, Lu Y, Bankson J, et al. Cellularand in vivo activity of a novel PI3K inhibitor, PX-866, against humanglioblastoma. Neuro Oncol 2010; 12: 559-69
66. Ihle NT, Lemos R, Schwartz D, Oh J, Halter RJ, Wipf P, et al. Peroxisomeproliferator-activated receptor gamma agonist pioglitazoneprevents the hyperglycemia caused by phosphatidylinositol3-kinasepathway inhibition by PX-866 without affecting antitumor activity.Mol Cancer Ther 2009; 8: 94-100
67. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, et al. Theidentification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GD-0941) as apotent, selective, orally bioavailable inhibitor of class I PI3 kinase forthe treatment of cancer. J Med Chem 2008; 51: 5522-32
68. Raynaud FI, Eccles SA, Patel S, Alix S, Box G, Chuckowree I, et al.Biological properties of potent inhibitors of class I phosphatidylinositide3- kinases: from PI-103 through PI-540, PI-620 to the oral agentGDC-0941. Mol Cancer Ther 2009; 8: 1725-38
69. Yao E, Zhou W, Lee-Hoeflich ST, Truong T, Haverty PM, Eastham-Anderson J, et al. Suppression of HER2/HER3-mediated growth ofbreast cancer cells with combinations of GDC-0941 PI3K inhibitor,trastuzumab, and pertuzumab. Clin Cancer Res 2009; 15: 4147-56
70. Wallin JJ, Guan J, Prior WW, Edgar KA, Kassees R, Sampath D, et al.Nuclear phospho-Akt increase predicts synergy of PI3K inhibition anddoxorubicin in breast and ovarian cancer. Sci Transl Med 2010; 2:48ra66
71. Garcia-Martinez JM, Wullschleger S, Preston G, Guichard S, FlemingS, Alessi DR, et al. Effect of PI3K-and mTOR-specific inhibitors onspontaneous B-cell follicular lymphomas in PTEN/LKB1-deficientmice. Br J Cancer 2011; 104: 1116-25
72. Burrows N, Babur M, Resch J, Ridsdale S, Mejin M, Rowling EJ, et al.GDC-0941 inhibits metastatic characteristics of thyroid carcinomasby targeting both the phosphoinositide-3 kinase (PI3K) and hypoxiainduciblefactor- 1alpha (HIF-1alpha) pathways. J Clin EndocrinolMetab 2011; 96: E1934-43
73. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, DotsonJ, et al. Discovery of a potent, selective, and orally available class Iphosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin(mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. JMed Chem 2011; 54: 7579-87
74. Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activityin cancer models driven by the PI3K pathway. Mol Cancer Ther2011; 10: 2426-36
75. Dolly S. A first-in-human, phase l study to evaluate the dual PI3K/mTOR inhibitor GDC-0980 administered QD in patients with advancedsolid tumors or non-Hodgkin's lymphoma. ASCO Annual Meeting201076
76. Dehnhardt CM, Venkatesan AM, Delos Santos E, Chen Z, SantosO, Ayral-Kaloustian S, et al. Lead optimization of N-3-substituted7- morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402. JMed Chem 2010; 53: 798-810
77. Mallon R, Hollander I, Feldberg L, Lucas J, Soloveva V, Venkatesan A,et al. Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol3-kinase/ mammalian target of rapamycin inhibitor. Mol CancerTher 2010; 9: 976-84
78. Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos SantosO, Ayral-Kaloustian S, et al. Bis(morpholino-1,3,5-triazine) derivatives:potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/ mammalian target of rapamycin inhibitors: discoveryof compound 26 (PKI-587), a highly efficacious dual inhibitor. J MedChem 2010; 53: 2636-45
79. Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, SantosED, et al. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res 2011; 17: 3193-203
80. Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T,et al. Identification of NVP-BKM120 as a potent, selective, orallybioavailable class I PI3 kinase inhibitor for treating cancer. ACS Med Chem Lett 2011; 2:774-9
81. Koul D, Fu J, Shen R, Lafortune TA, Wang S, Tiao N, et al. Antitumoractivity of NVP-BKM120-a selective pan class 1 PI3 Kinase inhibitorshowed differential forms of cell death based on P53 status ofglioma cells. Clin Cancer Res 2012; 18:184-95
82. Aziz SA, Jilaveanu LB, Zito C, Camp RL, Rimm DL, Conrad P, et al.Vertical targeting of the phosphatidylinositol-3 kinase pathway as astrategy for treating melanoma. Clin Cancer Res 2010; 16: 6029-39
83. Stauffer F, Maira SM, Furet P, Garcia-Echeverria C. Imidazo[4,5-c] quinolines as inhibitors of the PI3K/PKB-pathway. Bioorg Med ChemLett 2008; 18: 1027-30
84. Santiskulvong C, Konecny GE, Fekete M, Chen KY, Karam A, MulhollandD, et al. Dual targeting of phosphoinositide 3-kinase and mammaliantarget of rapamycin using NVP-BEZ235 as a novel therapeuticapproach in human ovarian carcinoma. Clin Cancer Res 2011; 17:2373-84
85. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, etal. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signalingand inhibits the growth of cancer cells with activating PI3K mutations.Cancer Res 2008; 68: 8022-30
86. Liu TJ, Koul D, LaFortune T, Tiao N, Shen RJ, Maira SM, et al. NVPBEZ235,a novel dual phosphatidylinositol 3-kinase/mammaliantarget of rapamycin inhibitor, elicits multifaceted antitumor activitiesin human gliomas. Mol Cancer Ther 2009; 8: 2204-10
87. McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, et al.Antimyeloma activity of the orally bioavailable dual phosphatidylinositol3- kinase/mammalian target of rapamycin inhibitor NVP-BEZ235.Cancer Res 2009; 69: 5835-42
88. Marone R, Erhart D, Mertz AC, Bohnacker T, Schnell C, CmiljanovicV, et al. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol Cancer Res 2009; 7:601-13
89. Baumann P, Mandl-Weber S, Oduncu F, Schmidmaier R. Thenovel orally bioavailable inhibitor of phosphoinositol-3-kinase andmammalian target of rapamycin, NVP-BEZ235, inhibits growth andproliferationin multiple myeloma. Exp Cell Res 2009; 315: 485-97
90. Konstantinidou G, Bey EA, Rabellino A, Schuster K, Maira MS, GazdarAF, et al. Dual phosphoinositide 3-kinase/mammalian target ofrapamycin blockade is an effective radiosensitizing strategy for thetreatment of non-small cell lung cancer harboring K-RAS mutations.Cancer Res 2009; 69: 7644-52
91. Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, etal. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVPBEZ235in HER2 amplified and PIK3CA mutant breast cancer cells.Proc Natl Acad Sci USA 2009; 106: 22299-304
92. Manara MC, Nicoletti G, Zambelli D, Ventura S, Guerzoni C, LanduzziL, et al. NVP-BEZ235 as a new therapeutic option for sarcomas. ClinCancer Res 2010; 16: 530-40
93. Bhatt AP, Bhende PM, Sin SH, Roy D, Dittmer DP, Damania B. Dualinhibitionof PI3K and mTOR inhibits autocrine and paracrine proliferativeloops in PI3K/Akt/mTOR-addicted lymphomas. Blood 2010;115: 4455-63
94. Roper J, Richardson MP, Wang WV, Richard LG, Chen W, Coffee EM,et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumorregression in a genetically engineered mouse model of PIK3CA wildtypecolorectal cancer. PLoS One 2011; 6: e25132
95. Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, etal. Preclinical modeling of combined phosphatidylinositol-3-kinaseinhibitionwith endocrine therapy for estrogen receptor-positivebreast cancer. Breast Cancer Res 2011; 13: R21
96. Baumann P, Schneider L, Mandl-Weber S, Oduncu F, Schmidmaier R.Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highlyeffective in multiple myeloma. Anticancer Drugs 2012; 23: 131-8
97. Chang KY, Tsai SY, Wu CM, Yen CJ, Chuang BF, Chang JY. Novelphosphoinositide 3-Kinase/mTOR dual inhibitor, NVP-BGT226,displays potent growthiinhibitory activity against human head andneck cancer cells in vitro and in vivo. Clin Cancer Res 2011; 17:7116-26
98. Shapiro GI, Edelman G, Calvo E, Aggarwal SK, Laird AD. Targetingaberrant PI3K pathway signaling with XL147, a potent, selective, andorally bioavailable PI3K inhibitor. Proc 97th Annu Meet AACR; 2007Apr 14-18; Los Angeles, CA. Abstract C205
99. Foster P. Potentiating the antitumor effects of chemotherapy with theselective PI3K inhibitor XL147; 19th AACR-NCI-EORTC Meeting; SanFrancisco, CA. 2007
100. Garcia-Echeverria C. Protein and lipid kinase inhibitors as targetedanticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways.Purinergic Signal 2009; 5: 117-25
101. Laird D. XL765 targets tumor growth, survival, and angiogenesisin preclinical models by dual inhibition of PI3K and mTOR (abstractB250). EORTC meeting 2007
102. Patnaik A, LoRusso P, Tabernero JA, Laird D, Aggarwal S,Papadopoulos K. Biomarker development for XL765, a potent andselectiveoral dual inhibitor of PI3K and mTOR currently beingadministered to patients in a phase I clinical trial (abstract B265).EORTC Meeting 2007
103. Mirzoeva OK, Hann B, Hom YK, Debnath J, Aftab D, Shokat K, et al.Autophagy suppression promotes apoptotic cell death in response toinhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma.J Mol Med (Berl) 2011; 89: 877-89
104. Winograd-Katz SE, Levitzki A. Cisplatin induces PKB/Akt activationand p38 (MAPK) phosphorylation of the EGF receptor. Oncogene2006; 25: 7381-90
105. Liu LZ, Zhou XD, Qian G, Shi X, Fang J, Jiang BH. AKT1 amplificationregulates cisplatin resistance in human lung cancer cells throughthe mammalian target of rapamycin/p70S6K1 pathway. Cancer Res2007; 67: 6325-32
106. Bellacosa A, Kumar CC, Di Cristofano A, Testa Jr. Activation of AKTkinases in cancer: implications for therapeutic targeting. Adv CancerRes 2005; 94: 29-86
107. Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducibleAkt activity promotes resistance to chemotherapy, trastuzumab, ortamoxifen in breast cancer cells. Mol Cancer Ther 2002; 1: 707-17
108. Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase B is constitutivelyactive in non-small cell lung cancer cells and promotes cellularsurvival and resistance to chemotherapy and radiation. CancerRes 2001; 61: 3986-97
109. Gajate C, Mollinedo F. Biological activities, mechanisms of actionand biomedical prospect of the antitumor ether phospholipid ET-18-OCH(3) (edelfosine), a proapoptotic agent in tumor cells. Curr DrugMetab 2002; 3: 491-525
110. Mollinedo F, Fernandez-Luna JL, Gajate C, Martin-Martin B, Benito A,Martinez-Dalmau R, et al. Selective induction of apoptosis in cancercells by the ether lipid ET-18-OCH3 (Edelfosine): molecular structurerequirements, cellular uptake, and protection by Bcl-2 and Bcl-X(L).Cancer Res 1997; 57: 1320-8
111. van der Luit AH, Vink SR, Klarenbeek JB, Perrissoud D, Solary E, VerheijM, et al. A new class of anticancer alkylphospholipids uses lipidrafts as membrane gateways to induce apoptosis in lymphoma cells.Mol Cancer Ther 2007; 6: 2337-45
112. Zaharieva MM, Konstantinov SM, Pilicheva B, Karaivanova M, Berger MR. Erufosine: a membrane targeting antineoplastic agent with signaltransduction modulating effects. Ann N Y Acad Sci 2007; 1095:182-92
113. Hilgard P, Klenner T, Stekar J, Nossner G, Kutscher B, Engel J.D-21266, a new heterocyclic alkylphospholipid with antitumour activity.Eur J Cancer 1997; 33: 442-6
114. Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK.Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.Mol Cancer Ther 2003; 2: 1093-103
115. Li Z, Tan F, Liewehr DJ, Steinberg SM, Thiele CJ. In vitro and in vivoinhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine.J Natl Cancer Inst 2010; 102: 758-70
116. Hennessy BT, Lu Y, Poradosu E, Yu Q, Yu S, Hall H, et al. Pharmacodynamicmarkers of perifosine efficacy. Clin Cancer Res 2007; 13:7421-31
117. Leleu X, Jia X, Runnels J, Ngo HT, Moreau AS, Farag M, et al. The Aktpathway regulates survival and homing in Waldenstrom macroglobulinemia.Blood 2007; 110: 4417-26
118. Kumar A, Fillmore HL, Kadian R, Broaddus WC, Tye GW, Van MeterTE. The alkylphospholipid perifosine induces apoptosis and p21-mediatedcell cycle arrest in medulloblastoma. Mol Cancer Res 2009; 7:1813-21
119. Porta C, Figlin RA. Phosphatidylinositol-3-kinase/Akt signaling pathwayand kidney cancer, and the therapeutic potential of phosphatidylinositol- 3-kinase/Akt inhibitors. J Urol 2009; 182: 2569-77
120. Engel JB, Honig A, Schonhals T, Weidler C, Hausler S, KrockenbergerM, et al. Perifosine inhibits growth of human experimental endometrialcancers by blockade of AKT phosphorylation. Eur J Obstet GynecolReprod Biol 2008; 141: 64-9
121. Floryk D, Thompson TC. Perifosine induces differentiation and celldeath in prostate cancer cells. Cancer Lett 2008; 266: 216-26
122. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, et al.Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt andinduces in vitro and in vivo cytotoxicity in human multiple myelomacells. Blood 2006; 107: 4053-62
123. Patel V, Lahusen T, Sy T, Sausville EA, Gutkind JS, Senderowicz AM.Perifosine, a novel alkylphospholipid, induces p21 (WAF1) expressionin squamous carcinoma cells through a p53-independent pathway,leading to loss in cyclin-dependent kinase activity and cell cycle arrest.Cancer Res 2002; 62: 1401-9
124. Bailey HH, Mahoney MR, Ettinger DS, Maples WJ, Fracasso PM, TraynorAM, et al. Phase II study of daily oral perifosine in patients withadvanced soft tissue sarcoma. Cancer 2006; 107: 2462-7
125. Elrod HA, Lin YD, Yue P, Wang X, Lonial S, Khuri FR, et al. The alkylphospholipidperifosine induces apoptosis of human lung cancercells requiring inhibition of Akt and activation of the extrinsic apoptoticpathway. Mol Cancer Ther 2007; 6: 2029-38
126. Fei HR, Chen G, Wang JM, Wang FZ. Perifosine induces cell cycle arrestand apoptosis in human hepatocellular carcinoma cell lines byblockade of Akt phosphorylation. Cytotechnology 2010; 62: 449-60
127. Vink SR, Schellens JH, Beijnen JH, Sindermann H, Engel J, DubbelmanR, et al. Phase I and pharmacokinetic study of combined treatmentwith perifosine and radiation in patients with advanced solidtumours. Radiother Oncol 2006; 80: 207-13
128. Ghobrial IM, Roccaro A, Hong F, Weller E, Rubin N, Leduc R, etal. Clinical and translational studies of a phase II trial of the noveloral Akt inhibitor perifosine in relapsed or relapsed/refractoryWaldenstrom's macroglobulinemia. Clin Cancer Res 2010; 16:1033-41
129. Knowling M, Blackstein M, Tozer R, Bramwell V, Dancey J, DoreN, et al. A phase II study of perifosine (D-21226) in patients withpreviously untreated metastatic or locally advanced soft tissuesarcoma: A National Cancer Institute of Canada Clinical Trials Grouptrial. Invest New Drugs 2006; 24: 435-9
130. Bendell JC, Nemunaitis J, Vukelja SJ, Hagenstad C, Campos LT,Hermann RC, et al. Randomized placebo-controlled phase II trialof perifosine plus capecitabine as second-or third-line therapy inpatients with metastatic colorectal cancer. J Clin Oncol 2011; 29:4394-400
131. Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D,et al. Perifosine plus bortezomib and dexamethasone in patientswith relapsed/refractory multiple myeloma previously treated withbortezomib: results of a multicenter phase I/II trial. J Clin Oncol2011; 29: 4243-9
132. Pitter KL, Galban CJ, Galban S, Tehrani OS, Li F, Charles N, et al.Perifosine and CCI 779 co-operate to induce cell death and decreaseproliferation in PTEN-intact and PTEN-deficient PDGF-driven murineglioblastoma. PLoS One 2011; 6: e14545
133. Sun H, Yu T, Li J. Co-administration of perifosine with paclitaxelsynergistically induces apoptosis in ovarian cancer cells: more thanjust AKT inhibition. Cancer Lett 2011; 310: 118-28
134. Berger MR, Tsoneva I, Konstantinov SM, Eibl H. Induction ofapoptosis by erucylphospho-N,N,N-trimethylammonium is associatedwith changes in signal molecule expressionand location. Ann N YAcad Sci 2003; 1010: 307-10
135. Hideshima T, Catley L, Raje N, Chauhan D, Podar K, Mitsiades C, etal. Inhibition of Akt induces significant downregulation of survivinand cytotoxicity in human multiple myeloma cells. Br J Haematol2007; 138: 783-91
136. Konstantinov SM, Eibl H, Berger MR. Alkylphosphocholines induceapoptosis in HL-60 and U-937 leukemic cells. Cancer ChemotherPharmacol 1998; 41: 210-6
137. Nieto-Miguel T, Gajate C, Mollinedo F. Differential targets andsubcellular localization of antitumor alkyl-lysophospholipid inleukemic versus solid tumor cells. J Biol Chem 2006; 281: 14833-40
138. Erdlenbruch B, Jendrossek V, Marx M, Hunold A, Eibl H, Lakomek M.Antitumor effects of erucylphosphocholine on brain tumor cells invitro and in vivo. Anticancer Res 1998; 18: 2551-7
139. Jendrossek V, Erdlenbruch B, Hunold A, Kugler W, Eibl H, LakomekM. Erucylphosphocholine, a novel antineoplastic ether lipid, blocksgrowth and induces apoptosis in brain tumor cell lines in vitro. Int JOncol 1999; 14: 15-22
140. Veenman L, Alten J, Linnemannstons K, Shandalov Y, Zeno S,Lakomek M, et al. Potential involvement of F0F1-ATP(synth)ase andreactive oxygen species in apoptosis induction by the antineoplasticagent erucylphosphohomocholine in glioblastoma cell lines : amechanism for induction of apoptosis via the 18 kDa mitochondrialtranslocator protein. Apoptosis 2010; 15: 753-68
141. Rudner J, Ruiner CE, Handrick R, Eibl HJ, Belka C, Jendrossek V. TheAkt-inhibitor Erufosine induces apoptotic cell death in prostate cancercells and increases the short term effects of ionizing radiation.Radiat Oncol 2010; 5: 108
142. Fiegl M, Lindner LH, Juergens M, Eibl H, Hiddemann W, Braess J.Erufosine, a novel alkylphosphocholine, in acute myeloid leukemia:single activity and combination with other antileukemic drugs.Cancer Chemother Pharmacol 2008; 62: 321-9
143. Martelli AM, Papa V, Tazzari PL, Ricci F, Evangelisti C, Chiarini F, etal. Erucylphosphohomocholine, the first intravenously applicablealkylphosphocholine, is cytotoxic to acute myelogenous leukemiacells through JNK-and PP2A-dependent mechanisms. Leukemia2010; 24: 687-98
144. Yosifov DY, Todorov PT, Zaharieva MM, Georgiev KD, PilichevaBA, Konstantinov SM, et al. Erucylphospho-N,N,N-trimethylpropylammonium(erufosine) is a potential antimyeloma drug devoid ofmyelotoxicity. Cancer Chemother Pharmacol 2011; 67: 13-25
145. Konigs SK, Pallasch CP, Lindner LH, Schwamb J, Schulz A, BrinkerR, et al. Erufosine, a novel alkylphosphocholine, induces apoptosisin CLL through a caspase-dependent pathway. Leuk Res 2010; 34:1064-9
146. Zeng Z, Samudio IJ, Zhang W, Estrov Z, Pelicano H, Harris D, et al.Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase3 signaling by a small-molecule KP372-1 induces mitochondrialdysfunction and apoptosis in acute myelogenous leukemia. CancerRes 2006; 66: 3737-46
147. Mandal M, Younes M, Swan EA, Jasser SA, Doan D, Yigitbasi O, etal. The Akt inhibitor KP372-1 inhibits proliferation and inducesapoptosis and anoikis in squamous cell carcinoma of the head andneck. Oral Oncol 2006; 42: 430-9
148. Koul D, Shen R, Bergh S, Sheng X, Shishodia S, Lafortune TA, et al.Inhibition of Akt survival pathway by a small-molecule inhibitor inhuman glioblastoma. Mol Cancer Ther 2006; 5: 637-44
149. Mandal M, Kim S, Younes MN, Jasser SA, El-Naggar AK, Mills GB, etal. The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferationand induces apoptosis in thyroid cancer cells. Br J Cancer2005; 92: 1899-905
150. Xi RG, Huang J, Li D, Wang XB, Wu LJ. Roles of PI3-K/Akt pathways innanoparticle realgar powders-induced apoptosis in U937 cells. ActaPharmacol Sin 2008; 29: 355-63
151. Feun LG, Savaraj N, Bodey GP, Lu K, Yap BS, Ajani JA, et al. Phase Istudy of tricyclic nucleoside phosphate using a five-day continuousinfusion schedule. Cancer Res 1984; 44: 3608-12
152. Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI, et al. Akt/proteinkinase B signaling inhibitor-2, a selective small molecule inhibitor ofAkt signaling with antitumor activity in cancer cells overexpressingAkt. Cancer Res 2004; 64: 4394-9
153. Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, et al. The Aktactivation inhibitor TCN-P inhibits Akt phosphorylation by bindingto the PH domain of Akt and blocking its recruitment to the plasmamembrane. Cell Death Differ 2010; 17: 1795-804
154. Powis G, Basseches PJ, Kroschel DM, Richardson RL, O'Connell MJ,Kvols LK. Disposition of tricyclic nucleoside-5′-monophosphate inblood and plasma of patients during phase I and II clinical trials.Cancer Treat Rep 1986; 70: 359-62
155. Noh KH, Kang TH, Kim JH, Pai SI, Lin KY, Hung CF, et al. Activation ofAkt as a mechanism for tumor immune evasion. Mol Ther 2009; 17:439-47
156. Schilcher RB, Haas CD, Samson MK, Young JD, Baker LH. Phase Ievaluation and clinical pharmacology of tricyclic nucleoside 5′-phosphateusing a weekly intravenous regimen. Cancer Res 1986; 46:3147-51
157. Feun LG, Blessing JA, Barrett RJ, Hanjani P. A phase II trial of tricyclicnucleoside phosphate in patients with advanced squamous cellcarcinoma
158. Heerding DA, Rhodes N, Leber JD, Clark TJ, Keenan RM, LafranceLV, et al. Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3- piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. JMed Chem 2008; 51: 5663-79
159. Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, LansingTJ, et al. Characterization of an Akt kinase inhibitor with potentpharmacodynamic and antitumor activity. Cancer Res 2008; 68:2366-74
160. Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, inducesgrowth inhibition and apoptosis in acute lymphoblastic leukemia celllines. Blood 2009; 113: 1723-9
161. Altomare DA, Zhang L, Deng J, Di Cristofano A, Klein-Szanto AJ,Kumar R, et al. GSK690693 delays tumor onset and progressionin genetically defined mouse models expressing activated Akt. ClinCancer Res 2010; 16: 486-96
162. Carol H, Morton CL, Gorlick R, Kolb EA, Keir ST, Reynolds CP, etal. Initial testing (stage 1) of the Akt inhibitor GSK690693 by thepediatric preclinical testing program. Pediatr Blood Cancer 2010;55: 1329-37
163. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, etal. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacyby standard chemotherapeutic agents or molecular targeted drugs invitro and in vivo. Mol Cancer Ther 2010; 9: 1956-67
164. Liu R, Liu D, Trink E, Bojdani E, Ning G, Xing M. The Akt-specificinhibitor MK2206 selectively inhibits thyroid cancer cells harboringmutations that can activate the PI3K/Akt pathway. J Clin EndocrinolMetab 2011; 96: E577-85
165. Knowles JA, Golden B, Yan L, Carroll WR, Helman EE, Rosenthal EL.Disruption of the AKT pathway inhibits metastasis in an orthotopicmodel of head and neck squamous cell carcinoma. Laryngoscope2011; 121: 2359-65
166. Meng J, Dai B, Fang B, Bekele BN, Bornmann WG, Sun D, et al.Combination treatment with MEK and AKT inhibitors is more effectivethan each drug alone in human non-small cell lung cancer in vitroand in vivo. PLoS One 2010; 5: e14124
167. Balasis ME, Forinash KD, Chen YA, Fulp WJ, Coppola D, HamiltonAD, et al. Combination of farnesyltransferase and Akt inhibitors issynergistic in breast cancer cells and causes significant breast tumorregression in ErbB2 transgenic mice. Clin Cancer Res 2011; 17:2852-62
168. Cheng Y, Zhang Y, Zhang L, Ren X, Huber-Keener KJ, Liu X, et al.MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinibagainst malignant glioma via modulating both autophagy and apoptosis.Mol Cancer Ther 2012; 11: 154-64
169. Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ, et al. Activationof phosphatidylinositol 3-kinase/Akt signaling pathway mediatesacquired resistance to sorafenib in hepatocellular carcinoma cells. JPharmacol Exp Ther 2011; 337: 155-61
170. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al.First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 inpatients with advanced solid tumors. J Clin Oncol 2011; 29:4688-95
171. Liu Y, Jiang N, Wu J, Dai W, Rosenblum JS. Polo-like kinases inhibitedby wortmannin. Labeling site and downstream effects. J Biol Chem2007; 282: 2505-11
172. Awasthi N, Yen PL, Schwarz MA, Schwarz RE. The efficacy of a novel,dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapyand antiangiogenic response in pancreatic cancer. J Cell Biochem2012; 113: 784-91
173. Roulin D, Waselle L, Dormond-Meuwly A, Dufour M, Demartines N,Dormond O. Targeting renal cell carcinoma with NVP-BEZ235, a dualPI3K/mTOR inhibitor, in combination with sorafenib. Mol Cancer2011; 10: 90
174. Xu CX, Li Y, Yue P, Owonikoko TK, Ramalingam SS, Khuri FR, et al.The combination of RAD001 and NVP-BEZ235 exerts synergisticanticancer activity against non-small cell lung cancer in vitro and invivo. PLoS One 2011; 6: e20899
175. Zitzmann K, Ruden J, Brand S, Goke B, Lichtl J, Spottl G, et al. Com pensatory activation of Akt in response to mTOR and Raf inhibitors-a rationale for dual-targeted therapy approaches in neuroendocrinetumor disease. Cancer Lett 2010; 295: 100-9
176. Leung E, Kim JE, Rewcastle GW, Finlay GJ, Baguley BC. Comparisonof the effects of the PI3K/mTOR inhibitors NVP-BEZ235 andGSK2126458 on tamoxifen-resistant breast cancer cells. CancerBiol Ther 2011; 11: 938-46
177. Dubrovska A, Elliott J, Salamone RJ, Kim S, Aimone LJ, Walker JR,et al. Combination therapy targeting both tumor-initiating anddifferentiated cell populations in prostate carcinoma. Clin CancerRes 2010; 16: 5692-702
178. Robinson JP, Vanbrocklin MW, Lastwika KJ, McKinney AJ, BrandnerS, Holmen SL. Activated MEK cooperates with Ink4a/Arf loss or Aktactivation to induce gliomas in vivo. Oncogene 2011; 30: 1341-50.