Signaling intermediates (MAPK and PI3K) as therapeutic targets in NSCLC

Current Pharmaceutical Design

Volumn 20, Issue 24, 2014, Pages 3944-3957

  Ciuffreda, Ludovica ^a   Incani, Ursula Cesta ^a   Steelman, Linda S ^b   Abrams, Stephen L ^b   Falcone, Italia ^a   Del Curatolo, Anaïs ^a   Chappell, William H ^b   Franklin, Richard A ^b   Vari, Sabrina ^a   Cognetti, Francesco ^a   Mccubrey, James A ^b   Milella, Michele ^a  

^a REGINA ELENA NATIONAL CANCER INSTITUTE   (Italy)

^b EAST CAROLINA UNIVERSITY   (United States)

Author keywords

Combination therapy; Crosstalk; Feedback loops; MAPK; NSCLC; PI3K

Indexed keywords

ANTINEOPLASTIC AGENT; B RAF KINASE; MAMMALIAN TARGET OF RAPAMYCIN; MEK PROTEIN; MEMBRANE PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; UNCLASSIFIED DRUG; PROTEIN KINASE INHIBITOR;

CANCER GENETICS; CANCER GROWTH; CANCER RESEARCH; CANCER THERAPY; HUMAN; INTRACELLULAR SIGNALING; LUNG CANCER; LUNG NON SMALL CELL CANCER; MOLECULAR BIOLOGY; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CARCINOMA, NON-SMALL-CELL LUNG; DRUG EFFECTS; LUNG NEOPLASMS; METABOLISM; PATHOLOGY;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CARCINOMA, NON-SMALL-CELL LUNG; HUMANS; LUNG NEOPLASMS; MITOGEN-ACTIVATED PROTEIN KINASES; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 84903977950     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/13816128113196660763     Document Type: Review

References (193)

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11-30.
2. Haber DA, Settleman J. Cancer: drivers and passengers. Nature 2007; 446: 145-146.
3. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519-525.
4. Davies H, Hunter C, Smith R, et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res 2005; 65: 7591-7595.
5. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 2006; 46: 249-279.
6. Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008; 14: 1351-1356.
7. Bria E, Di MM, Carlini P, et al. Targeting targeted agents: open issues for clinical trial design. J Exp Clin Cancer Res 2009; 28: 66.
8. Milella, M.; Ciuffreda, L.; Bria, E. In Macromolecular anticancer therapeutics; Harivardhan Reddy, L.; Couvreur, P., Eds.; Humana Press: New York, 2010; pp 37-83.
9. Bria E, Pilotto S, Bonomi M et al. Targeted agents (TA) for advanced solid tumors (AST): what is the likelihood of being helped or harmed (LHH)? Assessing the clinical impact of therapies with FDA/EMEA approval. J Clin Oncol 2013; 31 suppl
10. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
11. Johnson JL, Pillai S, Chellappan SP. Genetic and biochemical alterations in non-small cell lung cancer. Biochem Res Int 2012; 2012: 940405.
12. Schmid K, Oehl N, Wrba F, et al. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res 2009; 15: 4554-4560.
13. Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002; 418: 934.
14. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002; 62: 6997-7000.
15. Bansal A, Ramirez RD, Minna JD. Mutation analysis of the coding sequences of MEK-1 and MEK-2 genes in human lung cancer cell lines. Oncogene 1997; 14: 1231-1234.
16. Bromberg-White JL, Andersen NJ, Duesbery NS. MEK genomics in development and disease. Brief Funct Genomics 2012; 11: 300-310.
17. Marks JL, Gong Y, Chitale D, et al. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res 2008; 68: 5524-5528.
18. Ikenoue T, Kanai F, Hikiba Y, et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 2005; 65: 4562-4567.
19. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304: 554.
20. Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008; 68: 6913-6921.
21. Ji M, Guan H, Gao C, et al. Highly frequent promoter methylation and PIK3CA amplification in non-small cell lung cancer (NSCLC). BMC Cancer 2011; 11: 147.
22. Scrima M, De MC, Fabiani F, 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 2012; 7: e30427.
23. Dobashi Y, Kimura M, Matsubara H, et al. Molecular alterations in AKT and its protein activation in human lung carcinomas. Hum Pathol 2012; 43: 2229-2240.
24. Kohno T, Takahashi M, Manda R, et al. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer 1998; 22: 152-156.
25. Lee SY, Kim MJ, Jin G, et al. Somatic mutations in epidermal growth factor receptor signaling pathway genes in non-small cell lung cancers. J Thorac Oncol 2010; 5: 1734-1740.
26. Kohno M, Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann Med 2006; 38: 200-211.
27. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 2004; 4: 937-947.
28. Tortora G, Bianco R, Daniele G, et al. Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies. Drug Resist Updat 2007; 10: 81-100.
29. Lopez-Bergami P, Fitchman B, Ronai Z. Understanding signaling cascades in melanoma. Photochem Photobiol 2008; 84: 289-306.
30. Russo AE, Torrisi E, Bevelacqua Y, et al. Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol 2009; 34: 1481-1489.
31. Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res 1998; 74: 49-139.
32. Seger R, Krebs EG. The MAPK signaling cascade. FASEB J 1995; 9: 726-735.
33. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007; 7: 295-308.
34. Roskoski R, Jr. RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun 2010; 399: 313-317.
35. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004; 5: 875-885.
36. Rodriguez-Viciana P, Tetsu O, Tidyman WE, et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 2006; 311: 1287-1290.
37. Garnett MJ, Rana S, Paterson H, et al. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 2005; 20: 963-969.
38. Rushworth LK, Hindley AD, O'neill E, et al. Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol 2006; 26: 2262-2272.
39. Niault TS, Baccarini M. Targets of Raf in tumorigenesis. Carcinogenesis 2010; 31: 1165-1174.
40. Zeng L, Imamoto A, Rosner MR. Raf kinase inhibitory protein (RKIP): a physiological regulator and future therapeutic target. Exp Opin Ther Targets 2008; 12: 1275-1287.
41. Hmitou I, Druillennec S, Valluet A, et al. Differential regulation of B-raf isoforms by phosphorylation and autoinhibitory mechanisms. Mol Cell Biol 2007; 27: 31-43.
42. Marais R, Light Y, Paterson HF, et al. Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem 1997; 272: 4378-4383.
43. Weber CK, Slupsky JR, Herrmann C, et al. Mitogenic signaling ofRas is regulated by differential interaction with Raf isozymes. Oncogene 2000; 19: 169-176.
44. Galabova-Kovacs G, Catalanotti F, Matzen D, et al. Essential role of B-Raf in oligodendrocyte maturation and myelination during postnatal central nervous system development. J Cell Biol 2008; 180: 947-955.
45. Galabova-Kovacs G, Matzen D, Piazzolla D, et al. Essential role of B-Raf in ERK activation during extraembryonic development. Proc Natl Acad Sci USA 2006; 103: 1325-1330.
46. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949-954.
47. Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 2008; 118: 1739-1749.
48. Baitei EY, Zou M, Al-Mohanna F, et al. Aberrant BRAF splicing as an alternative mechanism for oncogenic B-Raf activation in thyroid carcinoma. J Pathol 2009; 217: 707-715.
49. Blasco RB, Francoz S, Santamaria D, et al. c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. Cancer Cell 2011; 19: 652-663.
50. Alessi DR, Saito Y, Campbell DG, et al. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J 1994; 13: 1610-1619.
51. Chambard JC, Lefloch R, Pouyssegur J, et al. ERK implication in cell cycle regulation. Biochim Biophys Acta 2006
52. McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2006
53. Campbell JS, Seger R, Graves JD, et al. The MAP kinase cascade. Recent Prog Horm Res 1995; 50: 131-159.
54. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001; 410: 37-40.
55. Freeman AK, Ritt DA, Morrison DK. Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. Mol Cell 2013; 49: 751-758.
56. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464: 431-435.
57. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010; 140: 209-221.
58. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011; 480: 387-390.
59. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-1657.
60. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7: 606-619.
61. Katso R, Okkenhaug K, Ahmadi K, et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001; 17: 615-675.
62. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008; 27: 5486-5496.
63. Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005; 4: 988-1004.
64. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27: 5497-5510.
65. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010; 28: 1075-1083.
66. Carpenter CL, Auger KR, Chanudhuri M, et al. Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem 1993; 268: 9478-9483.
67. Skolnik EY, Margolis B, Mohammadi M, et al. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 1991; 65: 83-90.
68. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006; 441: 424-430.
69. Damen JE, Liu L, Rosten P, et al. The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc Natl Acad Sci USA 1996; 93: 1689-1693.
70. Lioubin MN, Algate PA, Tsai S, et al. p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity. Genes Dev 1996; 10: 1084-1095.
71. Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7: 261-269.
72. Currie RA, Walker KS, Gray A, et al. Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J 1999; 337 (Pt 3): 575-583.
73. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 355-365.
74. Brazil DP, Yang ZZ, Hemmings BA. Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 2004; 29: 233-242.
75. Cho H, Thorvaldsen JL, Chu Q, et al. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 2001; 276: 38349-38352.
76. Arboleda MJ, Lyons JF, Kabbinavar FF, et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 2003; 63: 196-206.
77. Summers SA, Kao AW, Kohn AD, et al. The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. J Biol Chem 1999; 274: 17934-17940.
78. Cong LN, Chen H, Li Y, et al. Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol Endocrinol 1997; 11: 1881-1890.
79. Duronio V. The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J 2008; 415: 333-344.
80. Puc J, Keniry M, Li HS, et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 2005; 7: 193-204.
81. Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci 2002; 27: 462-467.
82. Kandel ES, Skeen J, Majewski N, et al. Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage. Mol Cell Biol 2002; 22: 7831-7841.
83. Fujita N, Sato S, Katayama K, et al. Akt-dependent phosphory-lation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem 2002; 277: 28706-28713.
84. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17: 596-603.
85. Mavrakis KJ, Zhu H, Silva RL, et al. Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev 2008; 22: 2178-2188.
86. Martelli AM, Evangelisti C, Chiarini F, et al. The phosphatidy-linositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 2010; 1: 89-103.
87. Fonseca BD, Smith EM, Lee VH, et al. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J Biol Chem 2007; 282: 24514-24524.
88. Wang L, Harris TE, Lawrence JC, Jr. Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J Biol Chem 2008; 283: 15619-15627.
89. Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-175.
90. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-1302.
91. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122-1128.
92. Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009; 137: 873-886.
93. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110: 177-189.
94. Kim DH, Sabatini DM. Raptor and mTOR: subunits of a nutrient-sensitive complex. Curr Top Microbiol Immunol 2004; 279: 259-270.
95. Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002; 10: 457-468.
96. Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25: 903-915.
97. Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007; 405: 513-522.
98. Woo SY, Kim DH, Jun CB, et al. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 2007; 282: 25604-25612.
99. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001; 15: 807-826.
100. Hardwick JS, Kuruvilla FG, Tong JK, et al. Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci USA 1999; 96: 14866-14870.
101. Powers T, Walter P. Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol Biol Cell 1999; 10: 987-1000.
102. Cybulski N, Hall MN. TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 2009; 34: 620-627.
103. Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 1999; 286: 1741-1744.
104. Karbowniczek M, Cash T, Cheung M, et al. Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. J Biol Chem 2004; 279: 29930-29937.
105. Im E, von Lintig FC, Chen J, et al. Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 2002; 21: 6356-6365.
106. Karbowniczek M, Robertson GP, Henske EP. Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization. J Biol Chem 2006; 281: 25447-25456.
107. Wennstrom S, Downward J. Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor. Mol Cell Biol 1999; 19: 4279-4288.
108. Vasudevan KM, Burikhanov R, Goswami A, et al. Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras. Cancer Res 2007; 67: 10343-10350.
109. Beck SE, Carethers JM. BMP suppresses PTEN expression via RAS/ERK signaling. Cancer Biol Ther 2007; 6: 1313-1317.
110. Roux PP, Ballif BA, Anjum R, et al. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 2004; 101: 13489-13494.
111. Ma L, Teruya-Feldstein J, Behrendt N, et al. Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression. Genes Dev 2005; 19: 1779-1786.
112. Ma L, Teruya-Feldstein J, Bonner P, et al. Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res 2007; 67: 7106-7112.
113. Carriere A, Cargnello M, Julien LA, et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol 2008; 18: 1269-1277.
114. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118: 3065-3074.
115. Yu CF, Liu ZX, Cantley LG. ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem 2002; 277: 19382-19388.
116. Ciuffreda L, Di SC, Cesta Inc, et al. The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms. J Mol Med (Berl) 2012; 90: 667-679.
117. She QB, Halilovic E, Ye Q, et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 2010; 18: 39-51.
118. Di NF, Arena S, Tabernero J, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010; 120: 2858-2866.
119. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010; 18: 683-695.
120. Kinkade CW, Castillo-Martin M, Puzio-Kuter A, et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 2008; 118: 3051-3064.
121. Grant S. Cotargeting survival signaling pathways in cancer. J Clin Invest 2008; 118: 3003-3006.
122. Bria E, Milella M, Cuppone F, et al. Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis. Ann Oncol 2011; 22: 2277-2285.
123. Garnett MJ, McDermott U. Exploiting genetic complexity in cancer to improve therapeutic strategies. Drug Discov Today 2012; 17: 188-193.
124. Yang W, Soares J, Greninger P, et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 2013; 41: D955-D961.
125. Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497: 108-112.
126. Campos-Parra AD, Zuloaga C, Manriquez ME, et al. KRAS Mutation as the Biomarker of Response to Chemotherapy and EGFR-TKIs in Patients With Advanced Non-Small Cell Lung Cancer: Clues For Its Potential Use in Second-Line Therapy Decision Making. Am J Clin Oncol 2013;
127. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2: e73.
128. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008; 9: 962-972.
129. Linardou H, Dahabreh IJ, Bafaloukos D, et al. Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol 2009; 6: 352-366.
130. Wislez M, Spencer ML, Izzo JG, et al. Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras. Cancer Res 2005; 65: 3226-3235.
131. Boffa DJ, Luan F, Thomas D, et al. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res 2004; 10: 293-300.
132. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006; 6: 729-734.
133. Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851-1863.
134. Chresta CM, Davies BR, Hickson I, 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 2010; 70: 288-298.
135. Liu TJ, Koul D, LaFortune T, et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 2009; 8: 2204-2210.
136. Molckovsky A, Siu LL. First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American society of clinical oncology meeting. J Hematol Oncol 2008; 1: 20.
137. Konstantinidou G, Bey EA, Rabellino A, 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 2009; 69: 7644-7652.
138. Xu CX, Zhao L, Yue P, et al. Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy. Cancer Biol Ther 2011; 12: 549-555.
139. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009; 9: 28-39.
140. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379: 1893-1901.
141. Wallace EM, Lyssikatos JP, Yeh T, et al. Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr Top Med Chem 2005; 5: 215-229.
142. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367: 107-114.
143. Yamaguchi T, Kakefuda R, Tajima N, et al. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int J Oncol 2011; 39: 23-31.
144. McCubrey JA, Steelman LS, Chappell WH, et al. Ras/Raf/MEK/ ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget 2012; 3: 1068-1111.
145. McCubrey JA, Steelman LS, Chappell WH, et al. Advances in targeting signal transduction pathways. Oncotarget 2012; 3: 1505-1521.
146. Pratilas CA, Hanrahan AJ, Halilovic E, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 2008; 68: 9375-9383.
147. Garon EB, Finn RS, Hosmer W, et al. Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. Mol Cancer Ther 2010; 9: 1985-1994.
148. Shannon AM, Telfer BA, Smith PD, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts. Clin Cancer Res 2009; 15: 6619-6629.
149. Garnett MJ, Edelman EJ, Heidorn SJ, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012; 483: 570-575.
150. Milella M, Precupanu CM, Gregorj C, et al. Beyond single pathway inhibition: MEK inhibitors as a platform for the development of pharmacological combinations with synergistic anti-leukemic effects. Curr Pharm Des 2005; 11: 2779-2795.
151. Corcoran RB, Cheng KA, Hata AN, et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 2013; 23: 121-128.
152. Tan N, Wong M, Nannini MA, et al. Bcl-2/Bcl-xL Inhibition Increases the Efficacy of Mek Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models. Mol Cancer Ther 2013;
153. Milella M, Estrov Z, Kornblau SM, et al. Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/ MAPK pathways in acute myelogenous leukemia. Blood 2002; 99: 3461-3464.
154. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10: 375-388.
155. Konopleva M, Milella M, Ruvolo P, et al. MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. Leukemia 2012; 26: 778-787.
156. Cragg MS, Jansen ES, Cook M, et al. Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J Clin Invest 2008; 118: 3651-3659.
157. Ciuffreda L, McCubrey JA, Milella M. Signaling Intermediates (PI3K/PTEN/AKT/mTOR and RAF/MEK/ERK Pathways) as Therapeutic Targets for Anti-Cancer and Anti Angiogenesis Treatments. Curr Signal Transd Therapy 2009; 4: 130-143.
158. Holt SV, Logie A, Davies BR, et al. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). Cancer Res 2012; 72: 1804-1813.
159. Legrier ME, Yang CP, Yan HG, et al. Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. Cancer Res 2007; 67: 11300-11308.
160. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2012; 2: 227-235.
161. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483: 100-103.
162. Ercan D, Xu C, Yanagita M, et al. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov 2012; 2: 934-947.
163. Huang MH, Lee JH, Chang YJ, et al. MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib. Mol Oncol 2013; 7: 112-120.
164. Cortot AB, Repellin CE, Shimamura T, et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res 2013; 73: 834-843.
165. Dy GK, Hillman SL, Rowland KM, Jr., et al. A front-line window of opportunity phase 2 study of sorafenib in patients with advanced nonsmall cell lung cancer: North Central Cancer Treatment Group Study N0326. Cancer 2010; 116: 5686-5693.
166. Blumenschein GR, Jr., Gatzemeier U, Fossella F, et al. Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. J Clin Oncol 2009; 27: 4274-4280.
167. Wakelee HA, Lee JW, Hanna NH, et al. A double-blind randomized discontinuation phase-II study of sorafenib (BAY 43-9006) in previously treated non-small-cell lung cancer patients: eastern cooperative oncology group study E2501. J Thorac Oncol 2012; 7: 1574-1582.
168. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 2011; 1: 44-53.
169. Gridelli C, Morgillo F, Favaretto A, et al. Sorafenib in combination with erlotinib or with gemcitabine in elderly patients with advanced non-small-cell lung cancer: a randomized phase II study. Ann Oncol 2011; 22: 1528-1534.
170. Spigel DR, Burris HA, III, Greco FA, et al. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011; 29: 2582-2589.
171. Scagliotti G, Novello S, Von PJ, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 1835-1842.
172. Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 2012; 30: 3084-3092.
173. Rinehart J, Adjei AA, LoRusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 2004; 22: 4456-4462.
174. Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res 2010; 16: 2450-2457.
175. Hainsworth JD, Cebotaru CL, Kanarev V, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 2010; 5: 1630-1636.
176. Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013; 14: 38-47.
177. Becerra C, Infante JR, Lawrence EG et al. A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors. J Clin Oncol 2012; 30: Abstr 3023.
178. Papadimitrakopoulou V. Development of PI3K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer. J Thorac Oncol 2012; 7: 1315-1326.
179. Wojtalla A, Arcaro A. Targeting phosphoinositide 3-kinase signalling in lung cancer. Crit Rev Oncol Hematol 2011; 80: 278-290.
180. Cohen RB, Janne PA, Engelman JA et al. A phase I safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients (pts) with advanced solid tumors. J Clin Oncol 2010; 28 suppl: Abstr 3015.
181. Kondapaka SB, Singh SS, Dasmahapatra GP, et al. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2003; 2: 1093-103.
182. Lu W, Defeo-Jones D, Davis L et al. In vitro and in vivo antitumor activities of MK-2206, a new allosteric Akt inhibitor. AACR Meeting Abstract 2009; Abstr 3714.
183. Lyss AP, Morrell LE, Perry MC. Triciribine phosphate (TCN-P) in advanced non-small cell lung cancer (NSCLC): phase II trial. ASCO Mee Absrt 1996;
184. Tolcher AW, Baird RD, Patnaik A et al. A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors. J Clin Oncol 2011; 29 suppl: Abstr 3004.
185. Hidalgo M, Buckner JC, Erlichman C, 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: 5755-5763.
186. Reungwetwattana T, Molina JR, Mandrekar SJ, 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 2012; 7: 919-922.
187. Bryce AH, Rao R, Sarkaria J, et al. Phase I study of temsirolimus in combination with EKB-569 in patients with advanced solid tumors. Invest New Drugs 2012; 30: 1934-1941.
188. Soria JC, Shepherd FA, Douillard JY, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 2009; 20: 1674-1681.
189. Tarhini A, Kotsakis A, Gooding W, et al. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res 2010; 16: 5900-5907.
190. Ramalingam SS, Harvey RD, Saba N, et al. Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer. Cancer 2010; 116: 3903-3909.
191. Vansteenkiste J, Solomon B, Boyer M, 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 2011; 6: 2120-2129.
192. Price KA, Azzoli CG, Krug LM, et al. Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol 2010; 5: 1623-1629.
193. Riely GJ, Brahmer JR, Planchard D et al. A randomized discontinuation phase II trial of ridaforolimus in non-small cell lung cancer (NSCLC) patients with KRAS mutations. J Clin Oncol 2012; 30 suppl: Abstr 7531.