Targeting PI3K/Akt/mTOR signaling in cancer

Frontiers in Oncology

Volumn 4 APR, Issue , 2014, Pages

  Porta, Camillo ^a   Paglino, Chiara ^a   Mosca, Alessandra ^b  

^a FONDAZIONE IRCCS POLICLINICO SAN MATTEO   (Italy)

^b MAGGIORE DELLA CARITÀ HOSPITAL   (Italy)

Author keywords

Akt; Everolimus; Inhibitors; MTOR; Novel agents; PI3K; Ridaforolimus; Temsirolimus

Indexed keywords

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; 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; 8 [4 (1 AMINOCYCLOBUTYL) PHENYL] 9 PHENYL 1, 2, 4 TRIAZOLO [3, 4 F] [1, 6] NAPHTHYRIDIN 3 (2H) ONE; ALPHA INTERFERON; ANTINEOPLASTIC AGENT; BUPARLISIB; DACTOLISIB; DUVELISIB; ERUCYLPHOSPHOCHOLINE; EVEROLIMUS; EXEMESTANE; GDC 0032; GSK 2636771; IDELALISIB; MAMMALIAN TARGET OF RAPAMYCIN; MILTEFOSINE; OCTREOTIDE; PBI 05204; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PICTILISIB; PLACEBO; RAPAMYCIN; RIDAFOROLIMUS; RX 0201; SORAFENIB; SUNITINIB; TEMSIROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG; WORTMANNIN;

APOPTOSIS; AUTOPHOSPHORYLATION; BREAST CANCER; CELL CYCLE PROGRESSION; DRUG DOSE INCREASE; DRUG DOSE TITRATION; GENETIC TRANSCRIPTION; HUMAN; KIDNEY CARCINOMA; LUNG DISEASE; MANTLE CELL LYMPHOMA; METABOLIC DISORDER; NEOPLASM; NEUROENDOCRINE TUMOR; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PROGRESSION FREE SURVIVAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; REVIEW; SIGNAL TRANSDUCTION; SOMATIC MUTATION; STOMATITIS; TUMOR GROWTH;

EID: 84901008792     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2014.00064     Document Type: Review

References (73)

1. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev (1999) 13:2905-27. doi:10.1101/gad.13.22.2905.
2. Shaw RJ, Cantley LC. Ras, PI3K, and mTOR signalling controls tumor cell growth. Nature (2006) 441:424-30. doi:10.1038/nature04869.
3. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/Akt pathway for cancer drug discovery. Nat Rev Drug Discov (2005) 4:988-1004. doi:10.1038/nrd1902.
4. Chen YL, Law PY, Loh HH. Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy. Curr Med Chem Anticancer Agents (2005) 5:575-89. doi:10.2174/156801105774574649.
5. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem (1998) 67:481-507. doi:10.1146/annurev.biochem.67.1.481.
6. Fresno-Vara JA, Casado E, De Castro J, Cejas P, Belda-Iniesta C, Gonzales-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev (2004) 30:193-204. doi:10.1016/j.ctrv.2003.07.007.
7. Pawson T, Nash P. Protein-protein interactions define specificity in signal transduction. Genes Dev (2000) 14:1027-47.
8. Testa JR, Bellacosa A. Akt plays a central role in tumorigenesis. Proc Natl Acad Sci U S A (2001) 98:10983-5. doi:10.1073/pnas.211430998.
9. Chen X, Thakkar H, Tyan F, Gim S, Robinson H, Lee C, et al. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene (2001) 20:6073-7. doi:10.1038/sj.onc.1204736.
10. Hussain AR, Ahmed SO, Ahmed M, Khan OS, Al Abdulmohsen S, Platanias LC, et al. Cross-talk between NFkB and the PI3-kinase/Akt pathway can be targeted in primary effusion lymphoma (PEL) cell lines for efficient apoptosis. PLoS One (2012) 7:e39945. doi:10.1371/journal.pone.0039945.
11. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle (2003) 2:339-45. doi:10.4161/cc.2.4.433.
12. Kumar CC, Madison V. Akt crystal structure and Akt-specific inhibitors. Oncogene (2005) 24:7493-501. doi:10.1038/sj.onc.1209087.
13. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev (2004) 18:1926-45. doi:10.1101/gad.1212704.
14. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell (2004) 6:91-9. doi:10.1016/j.ccr.2004.06.007.
15. Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal (2009) 21:656-64. doi:10.1016/j.cellsig.2009.01.004.
16. Grewe M, Gansauge F, Schmid RM, Adler G, Seufferlein T. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res (1999) 59:3581-7.
17. Abraham RT. mTOR as a positive regulator of tumor cell responses to hypoxia. Curr Top Microbiol Immunol (2004) 279:299-319.
18. Lu Y, Lin YZ, LaPushin R, Cuevas B, Fang X, Yu SX, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene (1999) 18:7034-45. doi:10.1038/sj.onc.1203183.
19. Simpson L, Parson R. PTEN: life as a tumor suppressor. Exp Cell Res (2001) 264:29-41. doi:10.1006/excr.2000.5130.
20. Seghal SN, Baker H, Vézina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) (1975) 28:727-32. doi:10.7164/antibiotics.28.727.
21. Douros J, Suffnes M. New antitumor substances of natural origin. Cancer Treat Rev (1981) 8:63-87. doi:10.1016/S0305-7372(81)80006-0.
22. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov (2006) 5:671-88. doi:10.1038/nrd2062.
23. Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G, et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res (2006) 12:5755-63. doi:10.1158/1078-0432.CCR-06-0118.
24. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med (2007) 356:2271-81. doi:10.1056/NEJMoa066838.
25. Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol (2009) 27:3822-9. doi:10.1200/JCO.2008.20.7977.
26. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol (2008) 26:361-7. doi:10.1200/JCO.2007.12.0345.
27. Mita MM, Poplin E, Britten CD, Tap WD, Rubin EH, Scott BB, et al. Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma. Ann Oncol (2013) 24:1104-11. doi:10.1093/annonc/mds602.
28. Demetri GD, Chawla SP, Ray-Coquard I, Le Cesne A, Staddon AP, Milhem MM, et al. 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 (2013) 31:2485-92. doi:10.1200/JCO.2012.45.5766.
29. O'Donnell A, Faivre S, Burris HA III, Rea D, Papadimitrakopoulou V, Shand N, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol (2008) 26:1588-95. doi:10.1200/JCO.2007.14.0988.
30. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet (2008) 372:449-56. doi:10.1016/S0140-6736(08)61039-9.
31. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer (2010) 116:4256-65. doi:10.1002/cncr.25219.
32. Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, et al. Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer (2012) 48:333-9. doi:10.1016/j.ejca.2011.11.027.
33. Bracarda S, Hutson TE, Porta C, Figlin RA, Calvo E, Grünwald V, et al. Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis. Br J Cancer (2012) 106:1475-80. doi:10.1038/bjc.2012.89.
34. Porta C, Calvo E, Climent MA, Vaishampayan U, Osanto S, Ravaud A, et al. Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 trial. Eur Urol (2012) 61:826-33. doi:10.1016/j.eururo.2011.12.057.
35. Scoazec JY. Angiogenesis in neuroendocrine tumors: therapeutic applications. Neuroendocrinology (2013) 97:45-56. doi:10.1159/000338371.
36. Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, et al. Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology (1998) 32:133-8. doi:10.1046/j.1365-2559.1998.00321.x.
37. Villaume K, Blanc M, Gouysse G, Walter T, Couderc C, Nejjari M, et al. VEGF secretion by neuroendocrine tumor cells is inhibited by octreotide and by inhibitors of the PI3K/Akt/mTOR pathway. Neuroendocrinology (2010) 91:268-78. doi:10.1159/000289569.
38. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol (2008) 26:4311-8. doi:10.1200/JCO.2008.16.7858.
39. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol (2010) 28:69-76. doi:10.1200/JCO.2009.24.2669.
40. Yao JC, Pavel M, Phan AT, Kulke MH, Hoosen S, St Peter J, et al. Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab (2011) 96:3741-9. doi:10.1210/jc.2011-0666.
41. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hoersch D, Winkler RE, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomized, placebo-controlled, phase 3 study. Lancet (2011) 378:2005-12. doi:10.1016/S0140-6736(11)61742-X.
42. Yao JC, Hainsworth JD, Wolin EM, Pavel ME, Baudin E, Gross D, et al. Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus (E+O) or placebo (P+O) among patients with advanced neuroendocrine tumors (NET). J Clin Oncol (2012) 30(Suppl 4):A157.
43. Pavel M, Kidd M, Modlin I. Systemic therapeutic options for carcinoid. Semin Oncol (2013) 40:84-99. doi:10.1053/j.seminoncol.2012.11.003.
44. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med (2011) 364:514-23. doi:10.1056/NEJMoa1009290.
45. Yao JC, Tsuchihashi Z, Panneerselvam A, Winkler RE, Bugarini R, Pavel M. Effect of everolimus treatment on markers angiogenesis in patients with advanced pancreatic neuroendocrine tumours (pNET) results from the phase III RADIANT-3 study. Eur J Cancer (2011) 47(Suppl 1):S463. doi:10.1158/0008-5472.CAN-12-3923.
46. Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res (2013) 73:1449-53. doi:10.1158/0008-5472.CAN-12-3923.
47. Fedele P, Calvani N, Marino A, Orlando L, Schiavone P, Quaranta A, et al. Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going? Crit Rev Oncol Hematol (2012) 84:243-51. doi:10.1016/j.critrevonc.2012.03.004.
48. Baselga J, Campone M, Piccart M, Burris HA III, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med (2012) 366:520-9. doi:10.1056/NEJMoa1109653.
49. Astrinidis A, Henske EP. Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. Oncogene (2005) 24:7475-81. doi:10.1038/sj.onc.1209090.
50. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet (2013) 381:817-24. doi:10.1016/S0140-6736(12)61767-X.
51. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet (2013) 381:125-32. doi:10.1016/S0140-6736(12)61134-9.
52. Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer (2011) 47:1287-98. doi:10.1016/j.ejca.2011.02.014.
53. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell (2012) 149:274-93. doi:10.1016/j.cell.2012.03.017.
54. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol (2012) 12:325-38. doi:10.1038/nri3198.
55. Martini M, Ciraolo E, Gulluni F, Hirsch E. Targeting PI3K in cancer: any good news? Front Oncol (2013) 3:108. doi:10.3389/fonc.2013.00108.
56. Porta C, Figlin RA. Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer, and the therapeutic potential of phosphatidylinositol-3-kinase/ Akt inhibitors. J Urol (2009) 182:2569-77. doi:10.1016/j.juro.2009.08.085.
57. Martelli AM, Chiarini F, Evangelisti C, Cappellini A, Buontempo F, Bressanin D, et al. Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget (2012) 3:371-94.
58. Pal SK, Reckamp K, Yu H, Figlin RA. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs (2010) 19:1355-66. doi:10.1517/13543784.2010.520701.
59. Leonard R, Hardy J, van Tienhoven G, Houston S, Simmonds P, David M, et al. Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol (2001) 19:4150-9.
60. Tan J, Yu Q. Molecular mechanisms of tumor resistance to PI3K-mTOR targeted therapy. Chin J Cancer (2013) 32:376-9. doi:10.5732/cjc.012.10287.
61. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell (2006) 22:159-68. doi:10.1016/j.molcel.2006.03.029.
62. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K dependent feedback loop in human cancer. J Clin Invest (2008) 118:3065-74. doi:10.1172/JCI34739.
63. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res (2006) 66:1500-8. doi:10.1158/0008-5472.CAN-05-2925.
64. Tan J, Lee PL, Li Z, Jiang X, Lim YC, Hooi SC, et al. B55beta-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell (2010) 18:459-71. doi:10.1016/j.ccr.2010.10.021.
65. Ilic N, Utermark T, Widlund HR, Roberts TM. PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc Natl Acad Sci U S A (2011) 108:E699-708. doi:10.1073/pnas.1108237108.
66. Dang CV. Myc on the path to cancer. Cell (2012) 149:22-35. doi:10.1016/j.cell.2012.03.003.
67. Sommer EM, Dry H, Cross D, Guichard S, Davies BR, Alessi DR. Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. Biochem J (2013) 452:499-508. doi:10.1042/BJ20130342.
68. Rosich L, Xargay-Torrent S, López-Guerra M, Campo E, Colomer D, Roué G. Counteracting autophagy overcomes resistance to everolimus in mantle cell lymphoma. Clin Cancer Res (2012) 18:5278-89. doi:10.1158/1078-0432.CCR-12-0351.
69. Rosich L, Colomer D, Roue G. Autophagy controls everolimus (RAD001) activity in mantle cell lymphoma. Autophagy (2013) 9:115-7. doi:10.4161/auto.22483.
70. Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta (2010) 1806:220-9. doi:10.1016/j.bbcan.2010.07.003.
71. Logue JS, Morrison DK. Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Genes Dev (2012) 26:641-50. doi:10.1101/gad.186965.112.
72. Ribatti D. Novel angiogenesis inhibitors: addressing the issue of redundancy in the angiogenic signaling pathway. Cancer Treat Rev (2011) 37:344-52. doi:10.1016/j.ctrv.2011.02.002.
73. Abdollahi A, Folkman J. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat (2010) 13:16-28. doi:10.1016/j.drup.2009.12.001.