Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer

Biochemical Pharmacology

Volumn 90, Issue 3, 2014, Pages 197-207

  Fumarola, Claudia ^a   Bonelli, Mara A ^a   Petronini, Pier Giorgio ^a   Alfieri, Roberta R ^a  

^a UNIVERSITY OF PARMA   (Italy)

Author keywords

AKT; mTOR; NSCLC; PI3K; SQCLC

Indexed keywords

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; 4 [2 (4 AMINO 1,2,5 OXADIAZOL 3 YL) 1 ETHYL 7 (3 PIPERIDINYLMETHOXY) 1H IMIDAZO[4,5 C]PYRIDIN 4 YL] 2 METHYL 3 BUTYN 2 OL; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; AZD 8055; BINIMETINIB; BUPARLISIB; COPANLISIB; DOCETAXEL; EVEROLIMUS; GDC 0032; GSK 2636771; KU 0063794; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; NVP BYL 719; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PILARALISIB; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; RAPAMYCIN; RIDAFOROLIMUS; TEMSIROLIMUS; UNCLASSIFIED DRUG; XL 765;

APOPTOSIS; CANCER CHEMOTHERAPY; DRUG TARGETING; HUMAN; LUNG NON SMALL CELL CANCER; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

AKT; MTOR; NSCLC; PI3K; SQCLC;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CARCINOMA, NON-SMALL-CELL LUNG; DRUG RESISTANCE, NEOPLASM; ENZYME INHIBITORS; HUMANS; LUNG NEOPLASMS; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; PHOSPHATIDYLINOSITOL 3-KINASE; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84903891089     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2014.05.011     Document Type: Note

References (82)

1. J.A. Engelman Targeting PI3K signalling in cancer: opportunities, challenges and limitations Nat Rev Cancer 9 2009 550 562
2. J. Rodon, R. Dienstmann, V. Serra, and J. Tabernero Development of PI3K inhibitors: lessons learned from early clinical trials Nat Rev Clin Oncol 10 2013 143 153
3. T. Gao, J. Brognard, and A.C. Newton The phosphatase PHLPP controls the cellular levels of protein kinase C J Biol Chem 283 2008 6300 6311
4. J. Huang, and B.D. Manning The TSC1-TSC2 complex: a molecular switchboard controlling cell growth Biochem J 412 2008 179 190 (Pubitemid 351758225)
5. A. Efeyan, and D.M. Sabatini mTOR and cancer: many loops in one pathway Curr Opin Cell Biol 22 2010 169 176
6. M. Shimobayashi, and M.N. Hall Making new contacts: the mTOR network in metabolism and signalling crosstalk Nat Rev Mol Cell Biol 15 2014 155 162
7. L. Liu, and C.A. Parent Review series: TOR kinase complexes and cell migration J Cell Biol 194 2011 815 824
8. B. Vanhaesebroeck, J. Guillermet-Guibert, M. Graupera, and B. Bilanges The emerging mechanisms of isoform-specific PI3K signalling Nat Rev Mol Cell Biol 11 2010 329 341
9. M. Scrima, C. De Marco, F. Fabiani, R. Franco, G. Pirozzi, and G. Rocco et al. Signaling networks associated with AKT activation in non-small cell lung cancer (NSCLC): new insights on the role of phosphatydil-inositol-3 kinase PLoS One 7 2012 e30427
10. J.M. Spoerke, C. O'Brien, L. Huw, H. Koeppen, J. Fridlyand, and R.K. Brachmann et al. Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models Clin Cancer Res 18 2012 6771 6783
11. N. Rekhtman, P.K. Paik, M.E. Arcila, L.J. Tafe, G.R. Oxnard, and A.L. Moreira et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations Clin Cancer Res 18 2012 1167 1176
12. Dy GK, Vansteenkiste J, Thomas M, De Pas T, Grossi F, De Greve J, et al. Epidemiology of PI3K pathway alterations in patients with metastatic NSCLC: findings from the international BASALT-1 study. J Thorac Oncol 2013;8(Suppl. 2) [abstract O04.5].
13. L. Wang, H. Hu, Y. Pan, R. Wang, Y. Li, and L. Shen et al. PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup PLoS One 9 2014 e88291
14. A. Stjernstrom, C. Karlsson, O.J. Fernandez, P. Soderkvist, M.G. Karlsson, and L.K. Thunell Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung Cancer Med 2014
15. M. Ji, H. Guan, C. Gao, B. Shi, and P. Hou Highly frequent promoter methylation and PIK3CA amplification in non-small cell lung cancer (NSCLC) BMC Cancer 11 2011 147
16. J.E. Chaft, M.E. Arcila, P.K. Paik, C. Lau, G.J. Riely, and M.C. Pietanza et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling Mol Cancer Ther 11 2012 485 491
17. M. Cumberbatch, X. Tang, G. Beran, S. Eckersley, X. Wang, and R.P. Ellston et al. Identification of a subset of human non-small cell lung cancer patients with high PI3Kbeta and low PTEN expression, more prevalent in squamous cell carcinoma Clin Cancer Res 20 2014 595 603
18. G. Jin, M.J. Kim, H.S. Jeon, J.E. Choi, D.S. Kim, and E.B. Lee et al. PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers Lung Cancer 69 2010 279 283
19. N. Yanagawa, C. Leduc, D. Kohler, M.A. Saieg, T. John, and J. Sykes et al. Loss of phosphatase and tensin homolog protein expression is an independent poor prognostic marker in lung adenocarcinoma J Thorac Oncol 7 2012 1513 1521
20. J. Choi, J. Chen, S.L. Schreiber, and J. Clardy Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP Science 273 1996 239 242 (Pubitemid 26285890)
21. D.D. Sarbassov, S.M. Ali, S. Sengupta, J.H. Sheen, P.P. Hsu, and A.F. Bagley et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB Mol Cell 22 2006 159 168
22. D.J. Boffa, F. Luan, D. Thomas, H. Yang, V.K. Sharma, and M. Lagman et al. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer Clin Cancer Res 10 2004 293 300 (Pubitemid 38114192)
23. N. Miyake, H. Chikumi, M. Takata, M. Nakamoto, T. Igishi, and E. Shimizu Rapamycin induces p53-independent apoptosis through the mitochondrial pathway in non-small cell lung cancer cells Oncol Rep 28 2012 848 854
24. B. Chen, S. Yuping, and J. Ni Rapamycin decreases survivin expression to induce NSCLC cell apoptosis under hypoxia through inhibiting HIF-1alpha induction Mol Biol Rep 39 2012 185 191
25. K.W. Kim, L. Moretti, L.R. Mitchell, D.K. Jung, and B. Lu Combined Bcl-2/mammalian target of rapamycin inhibition leads to enhanced radiosensitization via induction of apoptosis and autophagy in non-small cell lung tumor xenograft model Clin Cancer Res 15 2009 6096 6105
26. Y. Gorzalczany, Y. Gilad, D. Amihai, I. Hammel, R. Sagi-Eisenberg, and O. Merimsky Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: a beneficial strategy to combat non-small cell lung cancer Cancer Lett 310 2011 207 215
27. X. Li, L.J. Tong, J. Ding, and L.H. Meng Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer Cancer Lett 342 2014 159 166
28. S.N. Waqar, P.K. Gopalan, K. Williams, S. Devarakonda, and R. Govindan A phase I trial of sunitinib and rapamycin in patients with advanced non-small cell lung cancer Chemotherapy 59 2013 8 13
29. J.C. Soria, F.A. Shepherd, J.Y. Douillard, J. Wolf, G. Giaccone, and L. Crino et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors Ann Oncol 20 2009 1674 1681
30. S. La Monica, M. Galetti, R.R. Alfieri, A. Cavazzoni, A. Ardizzoni, and M. Tiseo et al. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines Biochem Pharmacol 78 2009 460 468
31. I. Nakachi, K. Naoki, K. Soejima, I. Kawada, H. Watanabe, and H. Yasuda et al. The combination of multiple receptor tyrosine kinase inhibitor and mammalian target of rapamycin inhibitor overcomes erlotinib resistance in lung cancer cell lines through c-Met inhibition Mol Cancer Res 8 2010 1142 1151
32. S. Dong, X.C. Zhang, H. Cheng, J.Q. Zhu, Z.H. Chen, and Y.F. Zhang et al. Everolimus synergizes with gefitinib in non-small-cell lung cancer cell lines resistant to epidermal growth factor receptor tyrosine kinase inhibitors Cancer Chemother Pharmacol 70 2012 707 716
33. B. Besse, N. Leighl, J. Bennouna, V.A. Papadimitrakopoulou, N. Blais, and A.M. Traynor et al. Phase II study of everolimus-erlotinib in previously treated patients with advanced non-small-cell lung cancer Ann Oncol 25 2014 409 415
34. K.A. Price, C.G. Azzoli, L.M. Krug, M.C. Pietanza, N.A. Rizvi, and W. Pao et al. Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer J Thorac Oncol 5 2010 1623 1629
35. Y. Huang, Y. Chen, Q. Mei, S. Yu, and S. Xia Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds Oncol Rep 29 2013 2486 2492
36. E.J. Kim, J.H. Jeong, S. Bae, S. Kang, C.H. Kim, and Y.B. Lim mTOR inhibitors radiosensitize PTEN-deficient non-small-cell lung cancer cells harboring an EGFR activating mutation by inducing autophagy J Cell Biochem 114 2013 1248 1256
37. G. Iyer, A.J. Hanrahan, M.I. Milowsky, H. Al-Ahmadie, S.N. Scott, and M. Janakiraman et al. Genome sequencing identifies a basis for everolimus sensitivity Science 338 2012 221
38. A. Fuchs, K. Konig, L.C. Heukamp, J. Fassunke, J. Kirfel, and S. Huss et al. Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer Diagn Pathol 9 2014 48
39. I. Beuvink, A. Boulay, S. Fumagalli, F. Zilbermann, S. Ruetz, and T. O'Reilly et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation Cell 120 2005 747 759 (Pubitemid 40568794)
40. B. Markova, P.S. Hahnel, S. Kasper, S. Herbertz, M. Schuler, and F. Breitenbuecher Pharmacologic inhibition of mTOR antagonizes the cytotoxic activity of pemetrexed in non-small cell lung cancer J Cancer Res Clin Oncol 138 2012 545 554
41. J. Vansteenkiste, B. Solomon, M. Boyer, J. Wolf, N. Miller, and L. Di Scala et al. Everolimus in combination with pemetrexed in patients with advanced non-small cell lung cancer previously treated with chemotherapy: a phase I study using a novel, adaptive Bayesian dose-escalation model J Thorac Oncol 6 2011 2120 2129
42. N. Hanna, F.A. Shepherd, F.V. Fossella, J.R. Pereira, F. De Marinis, and J. von Pawel et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy J Clin Oncol 22 2004 1589 1597 (Pubitemid 41079796)
43. S.S. Ramalingam, T.K. Owonikoko, M. Behera, J. Subramanian, N.F. Saba, and S.A. Kono et al. Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced non-small-cell lung cancer J Thorac Oncol 8 2013 369 372
44. T. Ohara, M. Takaoka, S. Toyooka, Y. Tomono, T. Nishikawa, and Y. Shirakawa et al. Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells Cancer Sci 102 2011 1344 1349
45. T. Reungwetwattana, J.R. Molina, S.J. Mandrekar, K. Allen-Ziegler, K.M. Rowland, and N.F. Reuter et al. Brief report: a phase II "window-of- opportunity" frontline study of the MTOR inhibitor, temsirolimus given as a single agent in patients with advanced NSCLC, an NCCTG study J Thorac Oncol 7 2012 919 922
46. S.N. Waqar, C. Robinson, J. Bradley, B. Goodgame, M. Rooney, and K. Williams et al. A phase I study of temsirolimus and thoracic radiation in non-small-cell lung cancer Clin Lung Cancer 15 2014 119 123
47. V.M. Rivera, R.M. Squillace, D. Miller, L. Berk, S.D. Wardwell, and Y. Ning et al. Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens Mol Cancer Ther 10 2011 1059 1071
48. S.J. Fei, X.C. Zhang, S. Dong, H. Cheng, Y.F. Zhang, and L. Huang et al. Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells PLoS One 8 2013 e69104
49. C.M. Chresta, B.R. Davies, I. Hickson, T. Harding, S. Cosulich, and S.E. Critchlow 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 Cancer Res 70 2010 288 298
50. S.V. Holt, A. Logie, B.R. Davies, D. Alferez, S. Runswick, and S. Fenton et al. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055) Cancer Res 72 2012 1804 1813
51. Q. Liu, C. Xu, S. Kirubakaran, X. Zhang, W. Hur, and Y. Liu et al. Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR Cancer Res 73 2013 2574 2586
52. A.C. Faber, D. Li, Y. Song, M.C. Liang, B.Y. Yeap, and R.T. Bronson et al. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition Proc Natl Acad Sci U S A 106 2009 19503 19508
53. H.O. Jin, Y.H. Lee, J.A. Park, J.H. Kim, S.E. Hong, and H.A. Kim et al. Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition Biochem Biophys Res Commun 444 2014 502 508
54. C.X. Xu, L. Zhao, P. Yue, G. Fang, H. Tao, and T.K. Owonikoko et al. Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy Cancer Biol Ther 12 2011 549 555
55. G. Konstantinidou, E.A. Bey, A. Rabellino, K. Schuster, M.S. Maira, and A.F. Gazdar et al. Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations Cancer Res 69 2009 7644 7652
56. J. Acquaviva, D.L. Smith, J. Sang, J.C. Friedland, S. He, and M. Sequeira et al. Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib Mol Cancer Ther 11 2012 2633 2643
57. C.R. Zito, L.B. Jilaveanu, V. Anagnostou, D. Rimm, G. Bepler, and S.M. Maira et al. Multi-level targeting of the phosphatidylinositol-3-kinase pathway in non-small cell lung cancer cells PLoS One 7 2012 e31331
58. C.X. Xu, Y. Li, P. Yue, T.K. Owonikoko, S.S. Ramalingam, and F.R. Khuri et al. The combination of RAD001 and NVP-BEZ235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo PLoS One 6 2011 e20899
59. Salkeni MA, Rixe O, Karim NA, Ogara S, Feiler M, Moorthy G, et al. BEZ235 in combination with everolimus for advanced solid malignancies: preliminary results of a phase Ib-escalation study. J Clin Oncol 2013;31(Suppl.) [abstr e13518].
60. P.A. Janne, R.B. Cohen, A.D. Laird, S. Mace, J.A. Engelman, and R. Ruiz-Soto et al. 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 2014 316 323
61. N.T. Ihle, R. Williams, S. Chow, W. Chew, M.I. Berggren, and G. Paine-Murrieta et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling Mol Cancer Ther 3 2004 763 772 (Pubitemid 39193758)
62. N.T. Ihle, G. Paine-Murrieta, M.I. Berggren, A. Baker, W.R. Tate, and P. Wipf et al. The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts Mol Cancer Ther 4 2005 1349 1357
63. N.T. Ihle, R. Lemos Jr., P. Wipf, A. Yacoub, C. Mitchell, and D. Siwak et al. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance Cancer Res 69 2009 143 150
64. D.S. Hong, D.W. Bowles, G.S. Falchook, W.A. Messersmith, G.C. George, and C.L. O'Bryant et al. 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 2012 4173 4182
65. H. Ren, L. Zhao, Y. Li, P. Yue, X. Deng, and T.K. Owonikoko et al. The PI3 kinase inhibitor NVP-BKM120 induces GSK3/FBXW7-dependent Mcl-1 degradation, contributing to induction of apoptosis and enhancement of TRAIL-induced apoptosis Cancer Lett 338 2013 229 238
66. H. Ren, M. Chen, P. Yue, H. Tao, T.K. Owonikoko, and S.S. Ramalingam et al. The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo Cancer Lett 325 2012 139 146
67. J.C. Bendell, J. Rodon, H.A. Burris, M. de Jonge, J. Verweij, and D. Birle et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors J Clin Oncol 30 2012 282 290
68. Tan DSW, Lim KH, Tai WM, Ahmad A, Pan S, Ng QS, et al. A phase Ib safety and tolerability of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib in EGFR TKI-resistant NSCLC. J Clin Oncol 2013;31(Suppl.) [abstr 8107].
69. Z.Q. Zou, L.N. Zhang, F. Wang, J. Bellenger, Y.Z. Shen, and X.H. Zhang The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells Mol Med Rep 5 2012 503 508
70. G.I. Shapiro, J. Rodon, C. Bedell, E.L. Kwak, J. Baselga, and I. Brana et al. 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 2014 233 245
71. N. Liu, B.R. Rowley, C.O. Bull, C. Schneider, A. Haegebarth, and C.A. Schatz et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110alpha and p110delta activities in tumor cell lines and xenograft models Mol Cancer Ther 12 2013 2319 2330
72. S.M. Brachmann, J. Kleylein-Sohn, S. Gaulis, A. Kauffmann, M.J. Blommers, and M. Kazic-Legueux et al. Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations Mol Cancer Ther 11 2012 1747 1757
73. A.M. Gonzales-Angulo, D. Juric, G. Argiles, J.H.M. Schellens, H.A. Burris, and J. Berlin et al. Safety, pharmacokinetics and preliminary activity of the alpha-specific PI3K inhibitor BYL719: results from the first-in-human study J Clin Oncol 31 Suppl. 2013 [abstr 2531]
74. D. Juric, I. Krop, R.K. Ramanathan, J. Xiao, S. Sanabria, and T.R. Wilson et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in human phase Ia dose escalation study Cancer Res 73 suppl 1 2013 abstract LB-64.
75. P. Hilgard, T. Klenner, J. Stekar, G. Nossner, B. Kutscher, and J. Engel D-21266, a new heterocyclic alkylphospholipid with antitumour activity Eur J Cancer 33 1997 442 446 (Pubitemid 27168072)
76. H.A. Elrod, Y.D. Lin, P. Yue, X. Wang, S. Lonial, and F.R. Khuri et al. The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway Mol Cancer Ther 6 2007 2029 2038 (Pubitemid 47052493)
77. L. Fu, Y.A. Kim, X. Wang, X. Wu, P. Yue, and S. Lonial et al. Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy Cancer Res 69 2009 8967 8976
78. J. Meng, B. Dai, B. Fang, B.N. Bekele, W.G. Bornmann, and D. Sun et al. Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo PLoS One 5 2010 e14124
79. H. Hirai, H. Sootome, Y. Nakatsuru, K. Miyama, S. Taguchi, and K. Tsujioka et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo Mol Cancer Ther 9 2010 1956 1967
80. T.A. Yap, L. Yan, A. Patnaik, I. Fearen, D. Olmos, and K. Papadopoulos et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors J Clin Oncol 29 2011 4688 4695
81. V. Papadimitrakopoulou, I.I. Wistuba, J.J. Lee, A.S. Tsao, N. Kalhor, and F.V. Fossella et al. BATTLE-2 program:a biomarker-integrated targeted therapy study in previously treated patients with advanced NSCLC J Clin Oncol 31 Suppl. 2013 [abstract TPS8118]
82. E.H. Jeong, H.S. Choi, T.G. Lee, H.R. Kim, and C.H. Kim Dual inhibition of PI3K/Akt/mTOR pathway and role of autophagy in non-small cell lung cancer cells Tuberc Respir Dis (Seoul) 72 2012 343 351