PI-3-Kinase inhibitors in colorectal cancer

Current Cancer Drug Targets

Volumn 11, Issue 2, 2011, Pages 190-198

  Ihle, N T ^a   Powis, G ^a   Kopetz, S ^a  

^a UNIVERSITY OF TEXAS   (United States)

Author keywords

AKT; Colorectal cancer; KRAS; PI3K; PIK3CA; PTEN

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; ANTINEOPLASTIC AGENT; CAPECITABINE; ERLOTINIB; FLUOROURACIL; MK 2206; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEIN KINASE B; TYROSINE KINASE RECEPTOR; UNCLASSIFIED DRUG; XL 765;

ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER SURVIVAL; COLORECTAL CANCER; DRUG EFFICACY; ENZYME ACTIVATION; GENE MUTATION; HUMAN; METASTASIS; MONOTHERAPY; NONHUMAN; ONCOGENE K RAS; PHENOTYPE; TREATMENT RESPONSE;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; COLORECTAL NEOPLASMS; DRUG MONITORING; ENZYME ACTIVATION; ENZYME INHIBITORS; GENOTYPE; HUMANS; MUTATION; PHENOTYPE; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNAL TRANSDUCTION;

EID: 79551646109     PISSN: 15680096     EISSN: None     Source Type: Journal    
DOI: 10.2174/156800911794328448     Document Type: Article

References (88)

1. Cancer Facts and Figures 2008. Atlanta: American Cancer Society; 2008.
2. Kopetz, S.; Chang, G. J.; Overman, M. J.; Eng, C.; Sargent, D. J.; Larson, D. W.; Grothey, A.; Vauthey, J. N.; Nagorney, D. M.; McWilliams, R. R. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J. Clin. Oncol. 2009, 27, 3677-3683.
3. Davies, J. M.; Goldberg, R. M. First-line therapeutic strategies in metastatic colorectal cancer. Oncology (Williston Park) 2008, 22, 1470-1479.
4. Kobayashi, M.; Nagata, S.; Iwasaki, T.; Yanagihara, K.; Saitoh, I.; Karouji, Y.; Ihara, S.; Fukui, Y. Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase. Proc. Natl. Acad. Sci. U S A 1999, 96, 4874-4879.
5. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 2002, 296, 1655-1657.
6. Manning, B. D.; Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 2007, 129, 1261-1274.
7. Shaw, R. J.; Cantley, L. C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006, 441, 424-430.
8. Wieduwilt, M. J.; Moasser, M. M. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell. Mol. Life Sci. 2008, 65, 1566-1584.
9. Donovan, E. A.; Kummar, S. Role of insulin-like growth factor-1R system in colorectal carcinogenesis. Crit. Rev. Oncol. Hematol. 2008, 66, 91-98.
10. Rexer, B. N.; Engelman, J. A.; Arteaga, C. L. Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists. Cell Cycle 2009, 8, 18-22.
11. Walther, A.; Johnstone, E.; Swanton, C.; Midgley, R.; Tomlinson, I.; Kerr, D. Genetic prognostic and predictive markers in colorectal cancer. Nat. Rev. Cancer 2009, 9, 489-499.
12. Karapetis, C. S.; Khambata-Ford, S.; Jonker, D. J.; O'Callaghan, C. J.; Tu, D.; Tebbutt, N. C.; Simes, R. J.; Chalchal, H.; Shapiro, J. D.; Robitaille, S.; Price, T. J.; Shepherd, L.; Au, H. J.; Langer, C.; Moore, M. J.; Zalcberg, J. R. KRAS mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 2008, 359, 1757-1765.
13. Wistuba, I. I.; Behrens, C.; Albores-Saavedra, J.; Delgado, R.; Lopez, F.; Gazdar, A. F. Distinct KRAS mutation pattern characterizes signet ring cell colorectal carcinoma. Clin. Cancer Res. 2003, 9, 3615-3619.
14. Edkins, S.; O'Meara, S.; Parker, A.; Stevens, C.; Reis, M.; Jones, S.; Greenman, C.; Davies, H.; Dalgliesh, G.; Forbes, S.; Hunter, C.; Smith, R.; Stephens, P.; Goldstraw, P.; Nicholson, A.; Chan, T. L.; Velculescu, V. E.; Yuen, S. T.; Leung, S. Y.; Stratton, M. R.; Futreal, P. A. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol. Ther. 2006, 5, 928-932.
15. Gupta, S.; Ramjaun, A. R.; Haiko, P.; Wang, Y.; Warne, P. H.; Nicke, B.; Nye, E.; Stamp, G.; Alitalo, K.; Downward, J. Binding of ras to phosphoinositide 3-kinase p110alpha is required for rasdriven tumorigenesis in mice. Cell 2007, 129, 957-968.
16. Lim, K. H.; Counter, C. M. Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 2005, 8, 381-392.
17. Freeman, D. J.; Li, A. G.; Wei, G.; Li, H.-H.; Kertesz, N.; Lesche, R.; Whale, A. D.; Martinez-Diaz, H.; Rozengurt, N.; Cardiff, R. D.; Liu, X.; Wu, H. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 2003, 3, 117-130.
18. Jia, S.; Liu, Z.; Zhang, S.; Liu, P.; Zhang, L.; Lee, S. H.; Zhang, J.; Signoretti, S.; Loda, M.; Roberts, T. M.; Zhao, J. J. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 2008, 454, 776-779.
19. Wee, S.; Wiederschain, D.; Maira, S. M.; Loo, A.; Miller, C.; de- Beaumont, R.; Stegmeier, F.; Yao, Y. M.; Lengauer, C. PTENdeficient cancers depend on PIK3CB. Proc. Natl. Acad. Sci. U S A 2008, 105, 13057-13062.
20. Tamura, M.; Gu, J.; Takino, T.; Yamada, K. M. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130cas. Cancer Res. 1999, 59, 442-449.
21. Goel, A.; Nagasaka, T.; Arnold, C. N.; Inoue, T.; Hamilton, C.; Niedzwiecki, D.; Compton, C.; Mayer, R. J.; Goldberg, R.; Bertagnolli, M. M.; Boland, C. R. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology 2007, 132, 127-138.
22. Nassif, N. T.; Lobo, G. P.; Wu, X.; Henderson, C. J.; Morrison, C. D.; Eng, C.; Jalaludin, B.; Segelov, E. PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene 2004, 23, 617-628.
23. Danielsen, S. A.; Lind, G. E.; Bjornslett, M.; Meling, G. I.; Rognum, T. O.; Heim, S.; Lothe, R. A. Novel mutations of the suppressor gene PTEN in colorectal carcinomas stratified by microsatellite instability- and TP53 mutation- status. Hum. Mutat. 2008, 29, E252-262.
24. Chang, J. G.; Chen, Y. J.; Perng, L. I.; Wang, N. M.; Kao, M. C.; Yang, T. Y.; Chang, C. P.; Tsai, C. H. Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur. J. Cancer 1999, 35, 647-651.
25. Negoro, K.; Takahashi, S.; Kinouchi, Y.; Takagi, S.; Hiwatashi, N.; Ichinohasama, R.; Shimosegawa, T.; Toyota, T. Analysis of the PTEN gene mutation in polyposis syndromes and sporadic gastrointestinal tumors in Japanese patients. Dis. Colon Rectum. 2000, 43, S29-33.
26. Dicuonzo, G.; Angeletti, S.; Garcia-Foncillas, J.; Brugarolas, A.; Okrouzhnov, Y.; Santini, D.; Tonini, G.; Lorino, G.; De Cesaris, M.; Baldi, A. Colorectal carcinomas and PTEN/MMAC1 gene mutations. Clin. Cancer Res. 2001, 7, 4049-4053.
27. Sheffer, M.; Bacolod, M. D.; Zuk, O.; Giardina, S. F.; Pincas, H.; Barany, F.; Paty, P. B.; Gerald, W. L.; Notterman, D. A.; Domany, E. Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc. Natl. Acad. Sci. U S A 2009, 106, 7131-7136.
28. Guanti, G.; Resta, N.; Simone, C.; Cariola, F.; Demma, I.; Fiorente, P.; Gentile, M. Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis. Hum. Mol. Genet. 2000, 9, 283-287.
29. Zhou, X. P.; Loukola, A.; Salovaara, R.; Nystrom-Lahti, M.; Peltomaki, P.; de la Chapelle, A.; Aaltonen, L. A.; Eng, C. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am. J. Pathol. 2002, 161, 439-447.
30. Frattini, M.; Signoroni, S.; Pilotti, S.; Bertario, L.; Benvenuti, S.; Zanon, C.; Bardelli, A.; Pierotti, M. A. Phosphatase protein homologue to tensin expression and phosphatidylinositol-3 phosphate kinase mutations in colorectal cancer. Cancer Res. 2005, 65, 11227.
31. Ruzzo, A.; Graziano, F.; Canestrari, E.; Magnani, M. Molecular predictors of efficacy to anti-EGFR agents in colorectal cancer patients. Curr. Cancer Drug Targets 2010, 10, 68-79.
32. Loupakis, F.; Pollina, L.; Stasi, I.; Ruzzo, A.; Scartozzi, M.; Santini, D.; Masi, G.; Graziano, F.; Cremolini, C.; Rulli, E.; Canestrari, E.; Funel, N.; Schiavon, G.; Petrini, I.; Magnani, M.; Tonini, G.; Campani, D.; Floriani, I.; Cascinu, S.; Falcone, A. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J. Clin. Oncol. 2009, 27, 2622-2629.
33. Frattini, M.; Saletti, P.; Romagnani, E.; Martin, V.; Molinari, F.; Ghisletta, M.; Camponovo, A.; Etienne, L. L.; Cavalli, F.; Mazzucchelli, L. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br. J. Cancer 2007, 97, 1139-1145.
34. Jhawer, M.; Goel, S.; Wilson, A. J.; Montagna, C.; Ling, Y. H.; Byun, D. S.; Nasser, S.; Arango, D.; Shin, J.; Klampfer, L.; Augenlicht, L. H.; Perez-Soler, R.; Mariadason, J. M. PIK3CA mutation/ PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008, 68, 1953-1961.
35. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.; Riggins, G. J.; Willson, J. K.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004, 304, 554.
36. Bader, A. G.; Kang, S.; Vogt, P. K. Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc. Natl. Acad. Sci. U S A 2006, 103, 1475-1479.
37. Velho, S.; Oliveira, C.; Ferreira, A.; Ferreira, A. C.; Suriano, G.; Schwartz, S.; Jr.; Duval, A.; Carneiro, F.; Machado, J. C.; Hamelin, R.; Seruca, R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur. J. Cancer 2005, 41, 1649-1654.
38. Lievre, A.; Bachet, J. B.; Le Corre, D.; Boige, V.; Landi, B.; Emile, J. F.; Cote, J. F.; Tomasic, G.; Penna, C.; Ducreux, M.; Rougier, P.; Penault-Llorca, F.; Laurent-Puig, P. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66, 3992-3995.
39. Kato, S.; Iida, S.; Higuchi, T.; Ishikawa, T.; Takagi, Y.; Yasuno, M.; Enomoto, M.; Uetake, H.; Sugihara, K. PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int. J. Cancer 2007, 121, 1771-1778.
40. Simi, L.; Pratesi, N.; Vignoli, M.; Sestini, R.; Cianchi, F.; Valanzano, R.; Nobili, S.; Mini, E.; Pazzagli, M.; Orlando, C. Highresolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer. Am. J. Clin. Pathol. 2008, 130, 247-253.
41. Freeman, D. J.; Juan, T.; Reiner, M.; Hecht, J. R.; Meropol, N. J.; Berlin, J.; Mitchell, E.; Sarosi, I.; Radinsky, R.; Amado, R. G. Association of KRAS mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin. Colorectal Cancer 2008, 7, 184-190.
42. Nosho, K.; Kawasaki, T.; Ohnishi, M.; Suemoto, Y.; Kirkner, G. J.; Zepf, D.; Yan, L.; Longtine, J. A.; Fuchs, C. S.; Ogino, S. PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia 2008, 10, 534-541.
43. Barault, L.; Veyrie, N.; Jooste, V.; Lecorre, D.; Chapusot, C.; Ferraz, J. M.; Lievre, A.; Cortet, M.; Bouvier, A. M.; Rat, P.; Roignot, P.; Faivre, J.; Laurent-Puig, P.; Piard, F. Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int. J. Cancer 2008, 122, 2255-2259.
44. Kang, S.; Denley, A.; Vanhaesebroeck, B.; Vogt, P. K. Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. USA 2006, 103, 1289-1294.
45. Kobayashi, T.; Cohen, P. Activation of serum- and glucocorticoidregulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem. J. 1999, 339 (Pt 2), 319-328.
46. Zhao, J. J.; Liu, Z.; Wang, L.; Shin, E.; Loda, M. F.; Roberts, T. M. The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl. Acad. Sci. U S A 2005, 102, 18443-18448.
47. Jaiswal, B. S.; Janakiraman, V.; Kljavin, N. M.; Chaudhuri, S.; Stern, H. M.; Wang, W.; Kan, Z.; Dbouk, H. A.; Peters, B. A.; Waring, P.; Dela Vega, T.; Kenski, D. M.; Bowman, K. K.; Lorenzo, M.; Li, H.; Wu, J.; Modrusan, Z.; Stinson, J.; Eby, M.; Yue, P.; Kaminker, J. S.; de Sauvage, F. J.; Backer, J. M.; Seshagiri S. Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 2009, 16, 463-474.
48. Bleeker, F. E.; Felicioni, L.; Buttitta, F.; Lamba, S.; Cardone, L.; Rodolfo, M.; Scarpa, A.; Leenstra, S.; Frattini, M.; Barbareschi, M.; Grammastro, M. D.; Sciarrotta, M. G.; Zanon, C.; Marchetti, A.; Bardelli, A. AKT1E17K in human solid tumours. Oncogene 2008, 27, 5648-5650.
49. Carpten, J. D.; Faber, A. L.; Horn, C.; Donoho, G. P.; Briggs, S. L.; Robbins, C. M.; Hostetter, G.; Boguslawski, S.; Moses, T. Y.; Savage, S.; Uhlik, M.; Lin, A.; Du, J.; Qian, Y. W.; Zeckner, D. J.; Tucker-Kellogg, G.; Touchman, J.; Patel, K.; Mousses, S.; Bittner, M.; Schevitz, R.; Lai, M. H.; Blanchard, K. L.; Thomas, J. E. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007, 448, 439-444.
50. Blanco-Aparicio, C.; Renner, O.; Leal, J. F. M.; Carnero, A. PTEN, more than the AKT pathway. Carcinogenesis 2007, 28, 1379-1386.
51. Parsons, D. W.; Wang, T.-L.; Samuels, Y.; Bardelli, A.; Cummins, J. M.; DeLong, L.; Silliman, N.; Ptak, J.; Szabo, S.; Willson, J. K. V.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Lengauer, C.; Velculescu, V. E. Colorectal cancer: Mutations in a signalling pathway. Nature 2005, 436, 792-792.
52. Rychahou, P. G.; Kang, J.; Gulhati, P.; Doan, H. Q.; Chen, L. A.; Xiao, S. Y.; Chung, D. H.; Evers, B. M. AKT2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc. Natl. Acad. Sci. U S A 2008, 105, 20315-20320.
53. Carnero, A.; Blanco-Aparicio, C.; Renner, O.; Link, W.; Leal, J. F. M. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr. Cancer Drug Targets 2008, 8, 187-198.
54. Yamamoto, H.; Shigematsu, H.; Nomura, M.; Lockwood, W. W.; Sato, M.; Okumura, N.; Soh, J.; Suzuki, M.; Wistuba, I. I.; Fong, K. M.; Lee, H.; Toyooka, S.; Date, H.; Lam, W. L.; Minna, J. D.; Gazdar, A. F. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res. 2008, 68, 6913-6921.
55. Engelman, J. A.; Chen, L.; Tan, X.; Crosby, K.; Guimaraes, A. R.; Upadhyay, R.; Maira, M.; McNamara, K.; Perera, S. A.; Song, Y.; Chirieac, L. R.; Kaur, R.; Lightbown, A.; Simendinger, J.; Li, T.; Padera, R. F.; Garcia-Echeverria, C.; Weissleder, R.; Mahmood, U.; Cantley, L. C.; Wong, K. K. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 2008, 14, 1351-1356.
56. Ihle, N. T.; Lemos, R.; Jr.; Wipf, P.; Yacoub, A.; Mitchell, C.; Siwak, D.; Mills, G. B.; Dent, P.; Kirkpatrick, D. L.; Powis, G. 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. 2009, 69, 143-150.
57. Park, E. S.; Rabinovsky, R.; Carey, M.; Hennessy, B. T.; Agarwal, R.; Liu, W.; Ju, Z.; Deng, W.; Lu, Y.; Woo, H. G.; Kim, S.-B.; Cheong, J.-H.; Garraway, L. A.; Weinstein, J. N.; Mills, G. B.; Lee, J.-S.; Davies, M. A. Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set. Mol. Cancer Ther. 2010, 9, 257-267.
58. Li, X. H.; Zheng, H. C.; Takahashi, H.; Masuda, S.; Yang, X. H.; Takano, Y. PTEN expression and mutation in colorectal carcinomas. Oncol. Rep. 2009, 22, 757-764.
59. Di Nicolantonio, F.; Arena, S.; Tabernero, J.; Grosso, S.; Molinari, F.; Macarulla, T.; Russo, M.; Cancelliere, C.; Zecchin, D.; Mazzucchelli, L.; Sasazuki, T.; Shirasawa, S.; Geuna, M.; Frattini, M.; Baselga, J.; Gallicchio, M.; Biffo, S.; Bardelli, A. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J. Clin. Investig. 2010, 120, 2858-2866.
60. Ogino, S.; Nosho, K.; Kirkner, G. J.; Shima, K.; Irahara, N.; Kure, S.; Chan, A. T.; Engelman, J. A.; Kraft, P.; Cantley, L. C.; Giovannucci, E. L.; Fuchs, C. S. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J. Clin. Oncol. 2009, 27, 1477-1484.
61. Halilovic, E.; She, Q. B.; Ye, Q.; Pagliarini, R.; Sellers, W. R.; Solit, D. B.; Rosen, N. PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Res. 2010, 70, 6804-6814.
62. Baker, A. F.; Dragovich, T.; Ihle, N. T.; Williams, R.; Fenoglio- Preiser, C.; Powis, G. Stability of phosphoprotein as a biological marker of tumor signaling. Clin. Cancer Res. 2005, 11, 4338-4340.
63. Baselga, J. Skin as a surrogate tissue for pharmacodynamic end points: is it deep enough? Clin. Cancer Res. 2003, 9, 2389-2390.
64. Agulnik, M.; da Cunha Santos, G.; Hedley, D.; Nicklee, T.; Dos Reis, P. P.; Ho, J.; Pond, G. R.; Chen, H.; Chen, S.; Shyr, Y.; Winquist, E.; Soulieres, D.; Chen, E. X.; Squire, J. A.; Marrano, P.; Kamel-Reid, S.; Dancey, J.; Siu, L. L.; Tsao, M. S. Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J. Clin. Oncol. 2007, 25, 2184-2190.
65. Williams, R.; Baker, A. F.; Ihle, N. T.; Winkler, A. R.; Kirkpatrick, L.; Powis, G. The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling. Cancer Chemother. Pharmacol. 2006, 58, 444-450.
66. Markman, B.; LoRusso, P. M.; Patnaik, A.; Heath, E.; Laird, A. D.; van Leeuwen, B.; Papadopoulos, K. P.; Baselga, J. A phase 1 dose escalation study of the safety pharmacokinetics and pharmacodynamics of XL765, a novel inhibitor of PI3K and mTOR, administered orally to patients with solid tumors. EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics. 2008.
67. Bowers, R. K.; Marder, P.; Green, L. J.; Horn, C. L.; Faber, A. L.; Thomas, J. E. A platelet biomarker for assessing phosphoinositide 3-kinase inhibition during cancer chemotherapy. Mol. Cancer Ther. 2007, 6, 2600-2607.
68. Lenz, H. J.; Van Cutsem, E.; Khambata-Ford, S.; Mayer, R. J.; Gold, P.; Stella, P.; Mirtsching, B.; Cohn, A. L.; Pippas, A. W.; Azarnia, N.; Tsuchihashi, Z.; Mauro, D. J.; Rowinsky, E. K. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J. Clin. Oncol. 2006, 24, 4914-4921.
69. Hanna, N.; Lilenbaum, R.; Ansari, R.; Lynch, T.; Govindan, R.; Janne, P. A.; Bonomi, P. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J. Clin. Oncol. 2006, 24, 5253-5258.
70. Vermorken, J. B.; Trigo, J.; Hitt, R.; Koralewski, P.; Diaz-Rubio, E.; Rolland, F.; Knecht, R.; Amellal, N.; Schueler, A.; Baselga, J. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J. Clin. Oncol. 2007, 25, 2171-2177.
71. Foukas, L. C.; Claret, M.; Pearce, W.; Okkenhaug, K.; Meek, S.; Peskett, E.; Sancho, S.; Smith, A. J.; Withers, D. J.; Vanhaesebroeck, B. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 2006, 441, 366-370.
72. Luo, J.; Sobkiw, C. L.; Hirshman, M. F.; Logsdon, M. N.; Li, T. Q.; Goodyear, L. J.; Cantley, L. C. Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab. 2006, 3, 355-366.
73. Garofalo, R. S.; Orena, S. J.; Rafidi, K.; Torchia, A. J.; Stock, J. L.; Hildebrandt, A. L.; Coskran, T.; Black, S. C.; Brees, D. J.; Wicks, J. R.; McNeish, J. D.; Coleman, K. G. Severe diabetes, agedependent loss of adipose tissue, and mild growth deficiency in mice lacking AKT2/PKB beta. J. Clin. Investig. 2003, 112, 197-208.
74. Ihle, N. T.; Lemos, R.; Schwartz, D.; Oh, J.; Halter, R. J.; Wipf, P.; Kirkpatrick, L.; Powis, G. Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Mol. Cancer Ther. 2009, 8, 94-100.
75. Hoffman, K.; Holmes, F. A.; Fraschini, G.; Esparza, L.; Frye, D.; Raber, M. N.; Newman, R. A.; Hortobagyi, G. N. Phase I-II study: triciribine (tricyclic nucleoside phosphate) for metastatic breast cancer. Cancer Chemother. Pharmacol. 1996, 37, 254-258.
76. Markman, B.; Atzori, F.; Perez-Garcia, J.; Tabernero, J.; Baselga, J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann. Oncol. 2010, 21, 683-691.
77. Courtney, K. D.; Corcoran, R. B.; Engelman, J. A. The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 2010, 28, 1075-1083.
78. Gills, J. J.; Dennis, P. A. Perifosine: update on a novel AKT inhibitor. Curr. Oncol. Rep. 2009, 11, 102-110.
79. Ihle, N. T.; Williams, R.; Chow, S.; Chew, W.; Berggren, M. I.; Paine-Murrieta, G.; Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham, R.; Kirkpatrick, L.; Powis, G. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3- kinase signaling. Mol. Cancer Ther. 2004, 3, 763-772.
80. Foster, P. G. Potentiating the antitumor effects of chemotherapy with the selective PI3K inhibitor XL147. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2002, C199,
81. Huang, W. C.; Hung, M. C. Induction of AKT activity by chemotherapy confers acquired resistance. J. Formos Med. Assoc. 2009, 108, 180-194.
82. Surucu, B.; Bozulic, L.; Hynx, D.; Parcellier, A.; Hemmings, B. A. In vivo analysis of protein kinase B (PKB)/AKT regulation in DNA-PKcs-null mice reveals a role for PKB/AKT in DNA damage response and tumorigenesis. J. Biol. Chem. 2008, 283, 30025-30033.
83. Ihle, N. T.; Paine-Murrieta, G.; Berggren, M. I.; Baker, A.; Tate, W. R.; Wipf, P.; Abraham, R. T.; Kirkpatrick, D. L.; Powis, G. 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. 2005, 4, 1349-1357.
84. Nagata, Y.; Lan, K. H.; Zhou, X.; Tan, M.; Esteva, F. J.; Sahin, A. A.; Klos, K. S.; Li, P.; Monia, B. P.; Nguyen, N. T.; Hortobagyi, G. N.; Hung, M. C.; Yu, D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004, 6, 117-127.
85. Prenen, H.; De Schutter, J.; Jacobs, B.; De Roock, W.; Biesmans, B.; Claes, B.; Lambrechts, D.; Van Cutsem, E.; Tejpar, S. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin. Cancer Res. 2009, 15, 3184-3188.
86. Sartore-Bianchi, A.; Martini, M.; Molinari, F.; Veronese, S.; Nichelatti, M.; Artale, S.; Di Nicolantonio, F.; Saletti, P.; De Dosso, S.; Mazzucchelli, L.; Frattini, M.; Siena, S.; Bardelli, A. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009, 69, 1851-1857.
87. Chung, K. Y.; Shia, J.; Kemeny, N. E.; Shah, M.; Schwartz, G. K.; Tse, A.; Hamilton, A.; Pan, D.; Schrag, D.; Schwartz, L.; Klimstra, D. S.; Fridman, D.; Kelsen, D. P.; Saltz, L. B. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J. Clin. Oncol. 2005, 23, 1803-1810.
88. Benvenuti, S.; Frattini, M.; Arena, S.; Zanon, C.; Cappelletti, V.; Coradini, D.; Daidone, M. G.; Pilotti, S.; Pierotti, M. A.; Bardelli, A. PIK3CA cancer mutations display gender and tissue specificity patterns. Hum. Mutat. 2008, 29, 284-288.