New molecular targets in the treatment of NSCLC

Current Pharmaceutical Design

Volumn 19, Issue 30, 2013, Pages 5333-5343

  Schettino, Clorinda ^a   Bareschino, Maria Anna ^a   Sacco, Paola Claudia ^a   Maione, Paolo ^a   Rossi, Antonio ^a   Casaluce, Francesca ^a   Sgambato, Assunta ^a   Gridelli, Cesare ^a  

^a S G MOSCATI HOSPITAL   (Italy)

Author keywords

ALK; c MET; Crizotinib; EGFR; Erlotinib; Gefitinib; NSCLC; PI3K

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 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; 5 (2,6 DICHLOROBENZYLSULFONYL) 3 [3,5 DIMETHYL 4 [2 (1 PYRROLIDINYLMETHYL) 1 PYRROLIDINYLCARBONYL] 1H PYRROL 2 YLMETHYLENE] 1,3 DIHYDRO 2H INDOL 2 ONE; AFATINIB; ALANINE AMINOTRANSFERASE; AMUVATINIB; ANAPLASTIC LYMPHOMA KINASE; ANTINEOPLASTIC AGENT; ASPARTATE AMINOTRANSFERASE; BAY 806946; BUPARLISIB; CABOZANTINIB; CARBOPLATIN; CISPLATIN; CRIZOTINIB; DOCETAXEL; DS 5178; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; FORETINIB; GEFITINIB; GEMCITABINE; JNJ 38877605; K 252A; MGCD 265; MK 2461; N (3 CHLOROPHENYL) 3 [3,5 DIMETHYL 4 (4 METHYL 1 PIPERAZINYLCARBONYL) 1H PYRROL 2 YLMETHYLENE] 2,3 DIHYDRO N METHYL 2 OXO 1H INDOLE 5 SULFONAMIDE; ONARTUZUMAB; PACLITAXEL; PEMETREXED; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PLACEBO; PROTEIN KINASE B; SCATTER FACTOR RECEPTOR; SGX 523; TIVANTINIB; TRIACYLGLYCEROL LIPASE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACNE; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHENIA; CENTRAL NERVOUS SYSTEM METASTASIS; COUGHING; DECREASED APPETITE; DIARRHEA; DIZZINESS; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DRY SKIN; DYSGEUSIA; DYSPNEA; EDEMA; ENZYME ACTIVITY; EPIGASTRIC PAIN; ERYTHEMA; FATIGUE; FUSION GENE; GENE MUTATION; GENE REARRANGEMENT; GENE TRANSLOCATION; HAIR DISCOLORATION; HAND FOOT SYNDROME; HUMAN; HYPERGLYCEMIA; HYPERTENSION; HYPOKALEMIA; HYPOXIA; INSOMNIA; LUNG ADENOCARCINOMA; LUNG NON SMALL CELL CANCER; MOLECULAR PATHOLOGY; MOLECULARLY TARGETED THERAPY; MOOD DISORDER; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUTROPENIA; OVERALL SURVIVAL; PAIN; PARONYCHIA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEINURIA; PRURITUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; RECOMMENDED DRUG DOSE; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SINUS BRADYCARDIA; STOMATITIS; SURVIVAL TIME; THORAX PAIN; TREATMENT OUTCOME; TREATMENT RESPONSE; TRIACYLGLYCEROL LIPASE BLOOD LEVEL; TUMOR BLEEDING; VISUAL DISORDER; VOMITING;

ANTINEOPLASTIC AGENTS; CARCINOMA, NON-SMALL-CELL LUNG; DRUG DESIGN; ENZYME INHIBITORS; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS;

EID: 84881343615     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/13816128113199990343     Document Type: Review

References (104)

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA. Cancer J Clin 2008; 58: 71-96.
2. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: Sobering results. J Clin Oncol 2001; 19: 1734-42.
3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92-8.
4. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 13; 358: 1160-74.
5. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. U.S. Food and Drug. Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.
6. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501.
7. Normanno N, Bianco C, De Luca A, et al. Target-Based agent against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr Relat Cancer 2003; 10: 1-21.
8. Mendelson J. Blockade of receptors for growt factor: an anticancer therapy. Clin Cancer Res 2000; 6: 747-53.
9. Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000; 19: 3159-67.
10. Yarden Y, Sliwkowski MX. Untantling the ErbB signalling network. Nature Rev Mol Cell Biol 2001; 2: 127-37.
11. Kurie JM, Shin HJ, Lee JS, et al. Increased epidermal growth factor receptor expression in metaplastic bronchial epithelium. Clin Cancer Res 1996; 2: 1787-93.
12. Janne PA, Engelman JA, Johnson BE. Epidermal growth factor receptor mutations in non-small-cell lung cancer: Implications for treatment and tumor biology. J Clin Oncol 2005; 23: 3227-34.
13. Minkovsky N, Berezov. BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Curr Opin Investig Drugs 2008; 9: 1336-46.
14. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-57.
15. Lee J, Park K, Kim SW, et al. A randomized phase III trial of gefitinib (IRESSA) versus standard chemotherapy (gemcitabine plus cisplatin) as a first-line treatment for never-smokers with advanced ot metastatic adenocarcinoma of the lung [abstract PRS.4]. J Thorac Oncol 2009; 4: S283-4.
16. Han JY, Park K, Kim SW et al. First-SIGNAL: First-Line SingleAgent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung. J Clin Oncol 2012 1; 30: 1122-8.
17. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11: 121-8.
18. Mitsudomi T, Morita S, Yatabe Y. Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of theepidermal growth factor receptor (EGFR). J Clin Oncol 30, 2012 (suppl; abstr 7521)
19. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380-8.
20. Inoue A, Kobayashi K, Maemondo M et al. S. Sugawara, S. Final overall survival results of NEJ002, a phase III trial comparing ge fitinib to carboplatin (CBDCA) plus paclitaxel (TXL) as the first line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. J Clin Oncol 2011; 29: (suppl; abstr 7519).
21. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958-67.
22. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735-42.
23. Zhou C, Wu YL, Liu X, et al. Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr 7520)
24. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239-46.
25. Schuler MH, Planchard D, Yang JCH, et al. Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator's choice chemotherapy following progression on afatinib monotherapy. J Clin Oncol 30, 2012 (suppl; abstr 7557).
26. Kim JH, Grossi F, De Marinis F, et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: Interim subset analysis from a phase III trial. J Clin Oncol 30, 2012 (suppl; abstr 7558)
27. Yang JCH, Schuler MH, Yamamoto N, et al. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)
28. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 2008; 8: 11-23.
29. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase pathway in lung cancer. Clin Cancer Res 2011; 17: 2081-6.
30. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994; 263: 1281-4.
31. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non small-cell lung cancer. Nature 2007; 448: 561-6.
32. Tort F, Campo E, Pohlman B, Hsi E. Heterogeneity of genomic breakpoints in MSN-ALK translocations in anaplastic large cell lymphoma. Human Pathology 2004; 35: 1038-41.
33. Armstrong F, Lamant L, Hieblot C, Delsol G, Touriol C. TPM3ALK expression induces changes in cytoskeleton organisation and confers higher metastatic capacities than other ALK fusion proteins. European Journal of Cancer 2007; 43: 640-6.
34. Hernandez L, Pinyol M, Hernandez S, et al. TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood 1999; 94: 3265-8.
35. Cools J, Wlodarska I, Somers R, et al. Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes, Chromosomes & Cancer 2002; 34: 354-62.
36. Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clinical Cancer Research 2009; 15: 3143-9.
37. Mano H. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Science 2008; 99: 2349-55.
38. Houtman SH, Rutteman M, De Zeeuw CI, French PJ. Echinoderm microtubule-associated protein like protein 4, a member of the echinoderm microtubule-associated protein family, stabilizes microtubules. Neuroscience 2007; 144: 1373-82.
39. Choi YL, Takeuchi K, Soda M, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 2008; 68: 4971-6.
40. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008; 14: 4275-83.
41. McDermott U, Iafrate AJ, Gray NS, et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008; 68: 3389-95.
42. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007; 6: 3314-22.
43. Kwak EL, Camidge DR, Clark J, et al. Clinical activity observed in a phase I dose escalation trial of an oral c-MET and ALK inhibitor, PF-02341066. J Clin Oncol 2009; 27: Suppl: 148s.
44. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363: 1693-703.
45. Solomon B, Bang YJ, Camidge DR, et al. Timing of responses to crizotinib (PF-02341066) in anaplastic lymphoma kinase-positive patients with advanced non-small cell lung cancer. Presented at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; 2010 Nov 16-19; Berlin, Germany.
46. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 29, No 15_suppl (May 20 Supplement), 2011: 2501.
47. Shaw AT, Yeap BY, Solomon BJ, et al. Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 29, No 15_suppl (May 20 Supplement), 2011: 7507.
48. Kim DW, Ahn MJ, Shi Y, et al. Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr 7533).
49. Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). Presented at the 37th Congress of the European Society for Medical Oncology (ESMO), Vienna, Austria, September 28-October 2, 2012. Abstract LBA1.
50. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003; 4: 915-22.
51. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signalling through adapter proteins. Oncogene. 2000; 19: 5582-9.
52. Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-MET kinase inhibits c-MET-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003; 63: 7345-55.
53. Trusolino L, Bertotti A, Comoglio PM. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell 2001; 107: 643-54.
54. Tavian D, De Petro G, Benetti A, Portolani N, Giulini SM, Barlati S. u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. Int J Cancer 2000; 87: 644-49.
55. Brien LE, Tang K, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE (July 2004). ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. 2004; Dev Cell 7: 21-32.
56. Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995; 80: 179-85. http://en.wikipedia.org/wiki/Digital_object_identifier.
57. Gentile A, Trusolino L, Comoglio PM. The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev 2008; 27: 85-94.
58. Boccaccio C, Andò M, Tamagnone L, et al. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 1998; 391: 285-8.
59. Boccaccio C, Comoglio PM. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat. Rev. Cancer 2006; 6: 637-45.
60. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest 2002; 109: 863-867.
61. Qiao H, Hung W, Tremblay E, et al. Constitutive activation of met kinase in non-small-cell lung carcinomas correlates with anchorage-independent cell survival. J Cell Bioch 2002; 86: 665-77.
62. Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003; 63: 7345-55
63. Date K, Matsumoto K, Kuba K, et al. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene, 1998; 17: 3045-54
64. Atabey N, Gao Y, Yao ZJ, et al. Potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion and branching morphogenesis by antagonists of Grb2 Src homology 2 domain interactions. J. Biol. Chem 2001; 276: 14308-14.
65. Abounader R, Lal B, Luddy C, et al. In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. FASEB J 2002; 16: 108-110.
66. Michieli P, Mazzone M, Basilico C, et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell. 2004; 6: 61-73.
67. Munshi N, Jeay S, Li Y et al., ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther 2010; 9: 1544-53.
68. Adjei AA, Schwartz B, Garmey E. Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Oncologist. 2011; 16: 788-99.
69. Engelman JA, Zejnullahu K, Mitsudomi T, et al., MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316: 1039-43
70. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011; 3: 75ra26
71. Laux I, Goldman J, Just R, et al. Phase I dose escalation trial (ARQ 197-111) evaluating combination of selective c-Met inhibitor ARQ 197 and erlotinib. J. Clin Oncol 27: 15s, 2009 (suppl; abstr 3549).
72. Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol. 2011; 29: 3307-15.
73. Press release: arqule and daiichi sankyo announce discontinuation of phase 3 marquee clinical trial in non-small cell lung cancer Available from: http://www.daiichisankyo.com/news/20121001_412
74. Qian F., Engst S., Yamaguchi K., et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2209; 69: 8009-16.
75. Eder JP, Shapiro GI, Appleman LJ, et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothe lial growth factor receptor 2. Clin Cancer Res. 2010; 16: 3507-16.
76. Sennino B, Naylor RM, Tabruyn S.P et al. Reduction of tumor invasiveness and metastasis and prolongation of survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by XL184. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, November 15_19, 2009,Boston, Massachusetts: abstract A13.
77. Salgia, R., Sherman, S., Hong, D.S., Ng, C.S., Frye, J., Janisch, L. et al. (2008) A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). J Clin Oncol 26(Suppl), abstract 3522.
78. Wakelee HA, Gettinger SN, Engelman JA et al. (2010) A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib (E) in patients (pts) withnon-small cell lung cancer (NSCLC). J Clin Oncol 28(Suppl): abstract 3017.
79. Schoffski, P, Sgroi M, Burris HA et al. Phase 2 randomized discontinuation trial (RDT) of XL184 in patients (pts) with advanced solid tumors. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, November 16_19, 2010, Berlin,Germany: abstract 371.
80. Hellerstedt BA, Edelman G, Vogelzang NJ. Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 30, 2012 (suppl; abstr 7514)
81. Martens T, Schmidt NO, Eckerich C et al. A novelone-armed antic-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006; 12: 6144-6615
82. Jin H, Yang R, Zheng Z. et al. MetMAb, the one-armed 5D5 antic-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res 2008; 68: 4360-8.
83. Spigel DR, Ervin TJ, Ramlau, RD et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotini b in advanced NSCLC. J Clin Oncol. 2011; 29 (suppl; abstr 7505).
84. Yu W, Pandita A, Penuel E, et al. Exploratory biomarker analyses from OAM4558g: A placebo-controlled phase II study of erlotinib with or without MetMAb in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 29: 2011 (suppl; abstr 7529).
85. Spigel DR, Edelman MJ, Mok T et al. The MetLUNG study: A randomized, double-blind, phase III study of onartuzumab (Met-MAb) plus erlotinib versus placebo plus erlotinib in patients with advanced, MET-positive non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr TPS7616)
86. 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.
87. Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des 2010; 16: 34-44.
88. Xu CX, Jin H, Shin JY. Roles of protein kinase B/Akt in lung cancer. Front Biosci2010; 2: 1472-84.
89. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 31; 296: 1655-7.
90. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001; 17: 615-75.
91. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7: 606-19.
92. Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT-a major therapeutic target. Biochim Biophys Acta 2004; 1697: 3-16.
93. Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001; 61: 3986-97.
94. Tang JM, He QY, Guo RX, Chang XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer 2006; 51: 181-91.
95. Lim WT, Zhang WH, Miller CR et al. PTEN and phosphorylated AKT expression and prognosis in earlyand late-stage nonsmall cell lung cancer. Oncol Rep 2007; 17: 853-7
96. Paez J, Sellers WR. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signalling. Cancer Treat Res 2003; 115: 145-67.
97. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009; 8: 627-44.
98. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010; 28: 1075-83.
99. Ding L, Getz G, Wheeler DA et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008; 455: 1069-75.
100. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9: 550-62.
101. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 2008; 27: 5511-26.
102. Maira SM, Pecchi S, Huang A et al. Identification and characteri zation of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012; 11: 317-28.
103. Bendell JC, Rodon J, Burris HA 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 2012; 3: 282-90.
104. Safety and Efficacy of BKM120 in Patients With Metastatic Nonsmall Cell Lung Cancer. Available at http://clinicaltrials.gov/ct2/show/NCT01297491(STudiofaseIBKM120).