Signal transduction pathways of the epidermal growth factor receptor in colorectal cancer and their inhibition by small molecules

Current Medicinal Chemistry

Volumn 19, Issue 33, 2012, Pages 5735-5744

  Efferth, T ^a  

^a JOHANNES GUTENBERG UNIVERSITY   (Germany)

Author keywords

Kinases; Natural products; Oncogenes; Small molecules; Tumor suppressor genes

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; 2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; 2 MORPHOLINO 8 PHENYLCHROMONE; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; AZD 8055; BALANOL; BUPARLISIB; EPIDERMAL GROWTH FACTOR RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PICTILISIB; PROTEIN KINASE B; RAF PROTEIN; RAPAMYCIN; RAS PROTEIN; REGORAFENIB; SELUMETINIB; SORAFENIB; TIPIFARNIB; TRAMETINIB; TRICIRIBINE; VEMURAFENIB; WORTMANNIN;

COLORECTAL CANCER; DRUG EFFECT; DRUG MECHANISM; DRUG RESPONSE; GENE EXPRESSION PROFILING; GENE MUTATION; HUMAN; NONHUMAN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

ANIMALS; ANTINEOPLASTIC AGENTS; COLON; COLORECTAL NEOPLASMS; DRUG RESISTANCE, NEOPLASM; HUMANS; MOLECULAR TARGETED THERAPY; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECTUM; SIGNAL TRANSDUCTION; SMALL MOLECULE LIBRARIES;

EID: 84871262033     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712803988884     Document Type: Review

References (137)

1. Parkin, D. M.; Bray, F.; Ferlay, J.; Pisani, P. Global cancer statistics, 2002. CA Cancer J. Clin., 2005, 55(2), 74-108.
2. O'Connell, J. B.; Maggard, M. A.; Ko, C. Y. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J. Natl. Cancer Inst., 2004, 96(19), 1420-1425.
3. Vogelstein, B.; Fearon, E. R.; Hamilton, S. R.; Kern, S. E.; Preisinger, A. C.; Leppert, M.; Nakamura, Y.; White, R.; Smits, A. M.; Bos, J. L. Genetic alterations during colorectal-tumor development. N. Engl. J. Med., 1988, 319(9), 525-532.
4. Vivanco, I.; Mellinghoff, I. K. Epidermal growth factor receptor inhibitors in oncology. Curr. Opin. Oncol., 2010, 22(6), 573-578.
5. Chirieac, L. R.; Dacic, S. Targeted Therapies in Lung Cancer. Surg. Pathol. Clin., 2010, 3(1), 71-82.
6. Hu-Lieskovan, S.; Vallbohmer, D.; Zhang, W.; Yang, D.; Pohl, A.; Labonte, M. J.; Grimminger, P. P.; Hölscher, A. H.; Semrau, R.; Arnold, D.; Dellas, K.; Debucquoy, A.; Haustermans, K.; Machiels, J. P.; Sempoux, C.; Rödel, C.; Bracko, M.; Velenik, V.; Lenz, H. J. EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients. Clin. Cancer Res., 2011, 17(15), 5161-5169. Epub 2011 Jun. 14.
7. Laurent-Puig, P.; Cayre, A.; Manceau, G.; Buc, E.; Bachet, J. B.; Lecomte, T.; Rougier, P.; Lievre, A.; Landi, B.; Boige, V.; Ducreux, M.; Ychou, M.; Bibeau, F.; Bouché, O.; Reid, J.; Stone, S.; Penault-Llorca, F. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J. Clin. Oncol. 2009, 27(35), 5924-5930. Epub 2009 Nov. 2.
8. Sartore-Bianchi, A.; Bencardino, K.; Cassingena, A.; Venturini, F.; Funaioli, C.; Cipani, T.; Amatu, A.; Pietrogiovanna, L.; Schiavo, R.; Di Nicolantonio, F.; Artale, S.; Bardelli, A.; Siena, S. Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer. Cancer Treat. Rev., 2010, 36 Suppl 3, S1-5. Review.
9. Park, J. H.; Han, S. W.; Oh, D. Y.; Im, S. A.; Jeong, S. Y.; Park, K. J.; Kim, T. Y.; Bang, Y. J.; Park, J. G. Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR intron 1 CA status in both primary tumors and paired metastases in determining benefit from cetuximab therapy in colon cancer. Cancer Chemother. Pharmacol., 2011, 68(4), 1045-1055. Epub 2011 Feb. 22.
10. Azuma, M.; Danenberg, K. D.; Iqbal, S.; El-Khoueiry, A.; Zhang, W.; Yang, D.; Koizumi, W.; Saigenji, K.; Danenberg, P. V.; Lenz, H. J. Epidermal growth factor receptor and epidermal growth factor receptor variant III gene expression in metastatic colorectal cancer. Clin. Colorectal Cancer., 2006, 6(3), 214-218.
11. Schulze, W. X.; Deng, L.; Mann, M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol. Systems Biol., 2005, 1, 2005.0008.
12. Zarich, N.; Oliva, J. L.; Martínez, N.; Jorge, R.; Ballester, A.; Gutiérrez-Eisman, S.; García-Vargas, S.; Rojas, J. M. Grb2 is a negative modulator of the intrinsic Ras-GEF activity of hSos1. Mol. Biol. Cell, 2006, 17, 3591-3597.
13. Avruch, J.; Khokhlatchev, A.; Kyriakis, J. M.; Luo, Z.; Tzivion, G.; Vavvas, D.; Zhang, X. F. Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Rec. Progr. Hormone Res., 2001, 56, 127-155.
14. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer., 2003, 3(1), 11-22.
15. Pende, M.; Um, S. H.; Mieulet, V.; Sticker, M.; Goss, V. L.; Mestan, J.; Mueller, M.; Fumagalli, S.; Kozma, S. C.; Thomas, G. S6K1, (-/-)/S6K2 (-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell Biol., 2004, 24, 3112-3124.
16. Lièvre, A.; Bachet, J. B.; Le Corre, D.; Boige, V.; Landi, B.; Emile, J. F.; Côté, 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(8), 3992-3995.
17. Linardou, H.; Dahabreh, I. J.; Kanaloupiti, D.; Siannis, F.; Bafaloukos, D.; Kosmidis, P.; Papadimitriou, C. A.; Murray, S. 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 nonsmall-cell lung cancer and metastatic colorectal cancer. Lancet Oncol., 2008, 9(10), 962-972. Epub 2008 Sep. 17.
18. Roth, A. D.; Tejpar, S.; Delorenzi, M.; Yan, P.; Fiocca, R.; Klingbiel, D.; Dietrich, D.; Biesmans, B.; Bodoky, G.; Barone, C.; Aranda, E.; Nordlinger, B.; Cisar, L.; Labianca, R.; Cunningham, D.; Van Cutsem, E.; Bosman, F. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J. Clin. Oncol., 2010, 28(3), 466-474. Epub 2009 Dec. 14.
19. Worthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: Road maps to cancer. World J Gastroenterol 2007, 13, 3784-3791.
20. Allegra, C. J.; Jessup, J. M.; Somerfield, M. R.; Hamilton, S. R.; Hammond, E. H.; Hayes, D. F.; McAllister, P. K.; Morton, R. F.; Schilsky, R. L. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol., 2009, 27(12), 2091-2096. Epub 2009 Feb. 2. Review.
21. Rajagopalan, H.; Bardelli, A.; Lengauer, C.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature, 2002, 418, 934.
22. Davies, H.; Bignell, G. R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M. J.; Bottomley, W.; Davis, N.; Dicks, E.; Ewing, R.; Floyd, Y.; Gray, K.; Hall, S.; Hawes, R.; Hughes, J.; Kosmidou, V.; Menzies, A.; Mould, C.; Parker, A.; Stevens, C.; Watt, S.; Hooper, S.; Wilson, R.; Jayatilake, H.; Gusterson, B. A.; Cooper, C.; Shipley, J.; Hargrave, D.; Pritchard-Jones, K.; Maitland, N.; Chenevix-Trench, G.; Riggins, G. J.; Bigner, D. D.; Palmieri, G.; Cossu, A.; Flanagan, A.; Nicholson, A.; Ho, J. W.; Leung, S. Y.; Yuen, S. T.; Weber, B. L.; Seigler, H. F.; Darrow, T. L.; Paterson, H.; Marais, R.; Marshall, C. J.; Wooster, R.; Stratton, M. R.; Futreal, P. A. Mutations of the BRAF gene in human cancer. Nature, 2002, 417, 949-954.
23. Ikenoue, T.; Hikiba, Y.; Kanai, F.; Tanaka, Y.; Imamura, J.; Imamura, T.; Ohta, M.; Ijichi, H.; Tateishi, K.; Kawakami, T.; Aragaki, J.; Matsumura, M.; Kawabe, T.; Omata, M. Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res., 2003, 63(23), 8132-8137.
24. French, A. J.; Sargent, D. J.; Burgart, L. J.; Foster, N. R.; Kabat, B. F.; Goldberg, R.; Shepherd, L.; Windschitl, H. E.; Thibodeau, S. N. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin. Cancer Res., 2008, 14(11), 3408-3415.
25. Samowitz, W. S.; Sweeney, C.; Herrick, J.; Albertsen, H.; Levin, T. R.; Murtaugh, M. A.; Wolff, R. K.; Slattery, M. L. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005, 65(14), 6063-6069.
26. Minoo, P.; Moyer, M. P.; Jass, J. R. Role of BRAF-V600E in the serrated pathway of colorectal tumourigenesis. J. Pathol., 2007, 212, 124-133.
27. Hutchins, G.; Southward, K.; Handley, K.; Magill, L.; Beaumont, C.; Stahlschmidt, J.; Richman, S.; Chambers, P.; Seymour, M.; Kerr, D.; Gray, R.; Quirke, P. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J. Clin. Oncol., 2011, 29(10), 1261-1270. Epub 2011 Mar. 7.
28. Fransén, K.; Klintenäs, M.; Osterström, A.; Dimberg, J.; Monstein, H. J.; Söderkvist, P. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis, 2004, 25(4), 527-533.
29. Cully, M.; You, H.; Levine, A. J.; Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer, 2006, 6, 184-192.
30. Di Cristofano, A.; Pandolfi, P. P. The multiple roles of PTEN in tumor suppression. Cell, 2000, 100, 387-390.
31. Downward, J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin. Cell Biol., 1998, 10, 262-267.
32. Morgensztern, D.; McLeod, H. L. PI3K/Akt/mTOR pathway as a target for cancer therapy. Anti-Cancer Drugs, 2005, 16, 797-803.
33. LoPiccolo, J.; Blumenthal, G. M.; Bernstein, W. B.; Dennis, P. A. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist. Updat., 2008, 11, 32-50.
34. 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(5), 1851-1857.
35. James, G. L.; Goldstein, J. L.; Brown, M. S.; Rawson, T. E.; Somers, T. C.; McDowell, R. S.; Crowley, C. W.; Lucas, B. K.; Levinson, A. D.; Marsters, J. C. Jr. Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science, 1993, 260(5116), 1937-1942.
36. Sun, J.; Qian, Y.; Hamilton, A. D.; Sebti, S. M. Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res., 1995, 55(19), 4243-4247.
37. Caponigro, F.; Casale, M.; Bryce, J. Farnesyl transferase inhibitors in clinical development. Expert Opin. Investig. Drugs, 2003, 12(6), 943-954.
38. Siegel, R.; Ward, E.; Brawley, O.; Jemal, A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J. Clin. 2011, 61(4), 212-236. Epub 2011 Jun. 17.
39. Tsao, H.; Atkins, M. B.; Sober, A. J. Management of cutaneous melanoma. N. Engl. J. Med., 2004, 351(10), 998-1012.
40. Guo, J.; Si, L.; Kong, Y.; Flaherty, K. T.; Xu, X.; Zhu, Y.; Corless, C. L.; Li, L.; Li, H.; Sheng, X.; Cui, C.; Chi, Z.; Li, S.; Han, M.; Mao, L.; Lin, X.; Du, N.; Zhang, X.; Li, J.; Wang, B.; Qin, S. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J. Clin. Oncol., 2011, 29(21), 2904-2909. Epub 2011 Jun. 20.
41. Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch KH, Zopf D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011 Jul. 1;129(1):245-55.
42. Strumberg D, Scheulen ME, Schultheis B, Richly H, Frost A, Büchert M, Christensen O, Jeffers M, Heinig R, Boix O, Mross K. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012 [Epub ahead of print]
43. Troiani T, Martinelli E, Orditura M, De Vita F, Ciardiello F, Morgillo F. Beyond bevacizumab: new anti-VEGF strategies in colorectal cancer. Expert Opin Investig Drugs. 2012 [Epub ahead of print]
44. Johnson, M.;, Rizvi, N. A.; Ginsberg, M. S.; Miller, V. A.; Kris, M. G.; Pao, W. A Phase II trial of salirasib in patients with stage IIIB/IV lung adenocarcinoma enriched for KRAS mutations. J. Clin. Oncol., 2009, 27(15 Suppl.), 8012.
45. Patrawala S, Puzanov I. Vemurafenib (RG67204, PLX4032): a potent, selective BRAF kinase inhibitor. Future Oncol. 2012 May; 8(5):509-23.
46. Yang H, Higgins B, Kolinsky K, Packman K, Bradley WD, Lee RJ, Schostack K, Simcox ME, Kopetz S, Heimbrook D, Lestini B, Bollag G, Su F. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012 Feb. 1;72(3):779-89.
47. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Pelle PD, Dias-Santagata D, Hung KE, Flaherty KT, Piris A, Wargo JA, Settleman J, Mino-Kenudson M, Engelman JA. EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012 Mar; 2(3):227-235.
48. Atkins, M. B.; Kunkel, L.; Sznol, M.; Rosenberg, S. A. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J. Sci. Am., 2000, 6 Suppl 1, S11-14.
49. Jansen, B.; Schlagbauer-Wadl, H.; Kahr, H.; Heere-Ress, E.; Mayer, B. X.; Eichler, H.; Pehamberger, H.; Gana-Weisz, M.; Ben-David, E.; Kloog, Y.; Wolff, K. Novel Ras antagonist blocks human melanoma growth. Proc. Natl. Acad. Sci., U S A. 1999, 96(24), 14019-14024.
50. Smalley, K. S.; Eisen, T. G. Farnesyl thiosalicylic acid inhibits the growth of melanoma cells through a combination of cytostatic and pro-apoptotic effects. Int. J. Cancer, 2002, 98(4), 514-522.
51. Jaksch, M.; Múnera, J.; Bajpai, R.; Terskikh, A.; Oshima, R. G. Cell cycledependent variation of a CD133 epitope in human embryonic stem cell, colon cancer, and melanoma cell lines. Cancer Res., 2008, 68(19), 7882-7886.
52. Roesch, A.; Fukunaga-Kalabis, M.; Schmidt, E. C.; Zabierowski, S. E.; Brafford, P. A.; Vultur, A.; Basu, D.; Gimotty, P.; Vogt, T.; Herlyn, M. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell, 2010, 141(4), 583-594.
53. Boisvert-Adamo, K.; Aplin, A. E. Mutant B-RAF mediates resistance to anoikis via Bad and Bim. Oncogene, 2008, 27(23), 3301-3312.
54. Corcoran, R. B.; Dias-Santagata, D.; Bergethon, K.; Iafrate, A. J.; Settleman, J.; Engelman, J. A. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010 Nov. 23;3(149):ra84.
55. Poulikakos, P. I.; Zhang, C.; Bollag, G.; Shokat, K. M.; Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 2010, 464(7287), 427-430.
56. Heidorn, S. J.; Milagre, C.; Whittaker, S.; Nourry, A.; Niculescu-Duvas, I.; Dhomen, N.; Hussain, J.; Reis-Filho, J. S.; Springer, C. J.; Pritchard, C.; Marais, R. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell, 2010, 140(2), 209-21.
57. Paraiso, K. H.; Xiang, Y.; Rebecca, V. W.; Abel, E. V.; Chen, Y. A.; Munko, A. C.; Wood, E.; Fedorenko, I. V.; Sondak, V. K.; Anderson, A. R.; Ribas, A.; Palma, M. D.; Nathanson, K. L.; Koomen, J. M.; Messina, J. L.; Smalley, K. S. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res., 2011, 71(7), 2750-2760.
58. Sebolt-Leopold, J. S.; Bridges, A. J. Road to PD0325901 and beyond: the MEK inhibitor quest. In: Li R, Stafford JA, editors, Kinase Inhibitor Drugs. John Wiley and Sons, New York: 2009. p. 205-227.
59. Trujillo, J. I. MEK inhibitors: a patent review 2008-2010. Expert Opin. Ther. Pat., 2011, 21(7), 1045-1069. Epub 2011 May 9.
60. Yeh, J. J.; Routh, E. D.; Rubinas, T.; Peacock, J.; Martin, T. D.; Shen, X. J.; Sandler, R. S.; Kim, H. J.; Keku, T. O.; Der, C. J. KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. Mol. Cancer Ther., 2009, 8(4), 834-43.
61. Tentler, J. J.; Nallapareddy, S.; Tan, A. C.; Spreafico, A.; Pitts, T. M.; Morelli, M. P.; Selby, H. M.; Kachaeva, M. I.; Flanigan, S. A.; Kulikowski, G. N.; Leong, S.; Arcaroli, J. J.; Messersmith, W. A.; Eckhardt, S. G. Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. Mol. Cancer Ther., 2010, 9(12), 3351-3362.
62. Corcoran, R. B.; Dias-Santagata, D.; Bergethon, K.; Iafrate, A. J.; Settleman, J.; Engelman, J. A. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci. Signal, 2010, 3(149), ra84.
63. Jing, J.; Greshock, J.; Holbrook, J. D.; Gilmartin, A. G.; Zhang, X.; McNeil, E.; Conway, T.; Moy, C.; Laquerre, S.; Bachman, K. E.; Wooster, R.; Degenhardt, Y. Comprehensive Predictive Biomarker Analysis for MEK Inhibitor GSK1120212. Mol. Cancer Ther., 2011, Dec. 14. [Epub ahead of print]
64. Yuan, T. L.; Cantley, L. C. PI3K pathway alterations in cancer: variations on a theme. Oncogene, 2008, 27, 5497-5510.
65. Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Disc Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2009, 8, 627-644.
66. Ligresti, G.; Militello, L.; Steelman, L. S.; Cavallaro, A.; Basile, F.; Nicoletti, F.; Stivala, F.; McCubrey, J. A.; Libra, M. PIK3CA mutations in human solid tumors. Cell Cycle, 2009, 8, 1352-1358.
67. 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 in human cancers. Science, 2004, 304, 554.
68. 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(9), 1477-1484.
69. Janku, F.; Tsimberidou, A. M.; Garrido-Laguna, I.; Wang, X.; Luthra, R.; Hong, D. S.; Naing, A.; Falchook, G. S.; Moroney, J. W.; Piha-Paul, S. A.; Wheler, J. J.; Moulder, S. L.; Fu, S.; Kurzrock, R. PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol. Cancer Ther., 2011, 10(3), 558-565.
70. Workman, P.; Clarke, P. A.; Raynaud, F. I.; van Montfort, R. L. Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res., 2010, 70(6), 2146-2157.
71. Baggiolini, M.; Dewald, B.; Schnyder, J.; Ruch, W.; Cooper, P. H.; Payne, T. G. Inhibition of the phagocytosis-induced respiratory burst by the fungal metabolite wortmannin and some analogues. Exp. Cell Res., 1987, 169, 408-418.
72. Arcaro, A.; Wymann, M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3, 4, 5-trisphosphate in neutrophil response. Biochem. J., 1993, 296, 297-301.
73. Wymann, M. P.; Bulgarelli-Leva, G.; Zvelebil, M. J.; Pirola, L.; Vanhaesebroeck, B.; Waterfield, M. D.; Panayotou, G. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol. Cell Biol., 1996, 16, 1722-1733.
74. Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1- benzopyran-4-one (LY294002). J. Biol. Chem., 1994, 269, 5241-5248.
75. Vogt, P. K.; Gymnopoulos, M.; Hart, P. I. Jr. 3-kinase and cancer: changing accents. Curr. Opin. Genet. Dev., 2009, 19, 12-17.
76. Knight, Z. A.; Shokat, K. M. Chemically targeting the PI3K family. Biochem. Soc. Trans. 2007, 35, 245-249.
77. Bain, J.; McLauchlan, H.; Elliott, M.; Cohen, P. The specificities of protein kinase inhibitors. Biochem. J., 2003, 371, 199-204.
78. Garcia-Echeverria, C.; Sellers, W. R. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene, 2008, 27, 5511-5526.
79. Yap, T. A.; Garrett, M. D.; Walton, M. I.; Raynaud, F.; de Bono, J. S.; Workman, P. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls and promises. Curr. Opin. Pharmacol., 2008, 8, 393-412.
80. Drees, B. E.; Mills, G. B.; Rommel, C.; Prestwich, G. D. Therapeutic potential of phosphoinositide 3-kinase inhibitors. Exp. Opin. Ther., 2004, 14, 1354-3776.
81. Crabbe, T.; Welham, M. J.; Ward, S. G. The PI3K inhibitor arsenal: choose your weapon! Trends Biochem. Sci., 2007, 32, 450-456.
82. Wang, J.; Kuropatwinski, K.; Hauser, J.; Rossi, M. R.; Zhou, Y.; Conway, A.; Kan, J. L.; Gibson, N. W.; Willson, J. K.; Cowell, J. K.; Brattain, M. G. Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis. Mol. Cancer Ther., 2007, 6(3), 1143-1150.
83. Marone R, Cmiljanovic V, Giese B, Wymann M P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta. 2008 Jan; 1784(1):159-85.
84. Kong D, Yamori T. Advances in development of phosphatidylinositol 3-kinase inhibitors. Curr Med Chem. 2009;16(22):2839-54.
85. Haagensen EJ, Kyle S, Beale GS, Maxwell RJ, Newell DR. The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br J Cancer. 2012 Apr. 10;106(8):1386-94.
86. Mueller A, Bachmann E, Linnig M, Khillimberger K, Schimanski CC, Galle PR, Moehler M. Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines. Cancer Chemother Pharmacol. 2012 Jun; 69(6):1601-15.
87. Roper J, Richardson M P, Wang WV, Richard LG, Chen W, Coffee EM, Sinnamon MJ, Lee L, Chen PC, Bronson RT, Martin ES, Hung KE. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS One. 2011;6(9):e25132.
88. Manning, B. D.; Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell, 2007, 129(7), 1261-1274. Review.
89. Arboleda, M. J.; Lyons, J. F.; Kabbinavar, F. F.; Bray, M. R.; Snow, B. E.; Ayala, R.; Danino, M.; Karlan, B. Y.; Slamon, D. J. 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(1), 196-206.
90. Itoh, N.; Semba, S.; Ito, M.; Takeda, H.; Kawata, S.; Yamakawa, M. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer, 2002, 94(12), 3127-3134.
91. Roy, H. K.; Olusola, B. F.; Clemens, D. L.; Karolski, W. J.; Ratashak, A.; Lynch, H. T.; Smyrk, T. C. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis, 2002, 23(1), 201-205.
92. Milburn, C. C.; Deak, M.; Kelly, S. M.; Price, N. C.; Alessi, D. R.; Van Aalten, D. M. Binding of phosphatidylinositol 3, 4, 5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem. J. 2003, 375(Pt 3), 531-538.
93. García-Echeverría, C.; Traxler, P.; Evans, D. B. ATP site-directed competitive and irreversible inhibitors of protein kinases. Med. Res. Rev., 2000, 20(1), 28-57.
94. Noble, M. E.; Endicott, J. A.; Johnson, L. N. Protein kinase inhibitors: insights into drug design from structure. Science, 2004, 303(5665), 1800-1805. Review.
95. Lindsley, C. W. The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update. Curr. Top. Med. Chem., 2010, 10(4), 458-477. Review.
96. Breitenlechner, C. B.; Wegge, T.; Berillon, L.; Graul, K.; Marzenell, K.; Friebe, W. G.; Thomas, U.; Schumacher, R.; Huber, R.; Engh, R. A.; Masjost, B. Structure-based optimization of novel azepane derivatives as PKB inhibitors. J. Med. Chem., 2004, 47(6), 1375-1390.
97. Livnah, N. L.; Yechezkel, T.; Salitra, Y.; Perlmutter, B.; Ohne, O.; Cohen, I.; Litman, P.; Senderowitz, H. WO2003/010281, 2003.
98. Plosker, G. L.; Keam, S. J. Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer. Drugs, 2006, 66(4), 449-475. Review.
99. Yang, L.; Dan, H. C.; Sun, M.; Liu, Q.; Sun, X. M.; Feldman, R. I.; Hamilton, A. D.; Polokoff, M.; Nicosia, S. V.; Herlyn, M.; Sebti, S. M.; Cheng, J. Q. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res., 2004, 64(13), 4394-4399.
100. Lindsley, C. W.; Bogusky, M. J.; Leister, W. H.; McClain, R. T.; Robinson, R.; Barnett, S. F.; Defeo-Jones, D. III; Ross, C. W.; Hartman, G. D. Synthesis and biological evaluation of unnatural canthine alkaloids. Tetrahedron Lett., 2005, 46, 2779-2782.
101. Whyte, D. B.; Holbeck, S. L. Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem. Biophys. Res. Commun., 2006, 340(2), 469-475.
102. Shor, B.; Gibbons, J. J.; Abraham, R. T.; Yu, K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle, 2009, 8(23), 3831-3837.
103. Dowling, R. J.; Pollak, M.; Sonenberg, N. Current status and challenges associated with targeting mTOR for cancer therapy. BioDrugs, 2009, 23(2), 77-91.
104. Schenone, S.; Brullo, C.; Musumeci, F.; Radi, M.; Botta, M. ATP-competitive inhibitors of mTOR: an update. Curr. Med. Chem. 2011, 18(20), 2995-3014.
105. Vézina, C.; Kudelski, A.; Sehgal, S. N. Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo), 1975, 28(10), 721-726.
106. Abraham, R. T.; Gibbons, J. J. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin. Cancer Res., 2007, 13, 3109-3114.
107. Meric-Bernstam, F.; Gonzalez-Angulo, A. M. Targeting the mTOR signaling network for cancer therapy. J. Clin. Oncol., 2009, 27, 2278-2287.
108. Liu, Q.; Thoreen, C.; Wang, J.; Sabatini, D.; Gray, N. S. mTOR Mediated Anti-Cancer Drug Discovery. Drug Discov. Today Ther. Strateg., 2009, 6(2), 47-55.
109. Fan, Q. W.; Cheng, C. K.; Nicolaides, T. P.; Hackett, C. S.; Knight, Z. A.; Shokat, K. M.; Weiss, W. A. A Dual Phosphoinositide-3-Kinase/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma. Cancer Res., 2007, 67, 7960-7965.
110. Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.; Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.; Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.; Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.; Salphati, L.,; Sohal, S.; Ultsch, M. H.; Valenti, M.; Wallweber, H. J.; Wan, N. C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The Identification of 2-(1H-Indazol-4-yl)-6-(4- methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno [3, 2-d] pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer. J. Med. Chem., 2008, 51, 5522-5532.
111. Hennessy, B. T.; Gonzalez-Angulo, A. M.; Carey, M. S.; Mills, G. B. A systems approach to analysis of molecular complexity in breast cancer. Clin. Cancer Res., 2009, 15, 417-419.
112. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 2008, 455, 1061-1068.
113. Greenman, C.; Stephens, P.; Smith, R.; Dalgliesh, G. L.; Hunter, C.; Bignell, G.; Davies, H.; Teague, J.; Butler, A.; Stevens, C.; Edkins, S.; O'Meara, S.; Vastrik, I.; Schmidt, E. E.; Avis, T.; Barthorpe, S.; Bhamra, G.; Buck, G.; Choudhury, B.; Clements, J.; Cole, J.; Dicks, E.; Forbes, S.; Gray, K.; Halliday, K.; Harrison, R.; Hills, K.; Hinton, J.; Jenkinson, A.; Jones, D.; Menzies, A.; Mironenko, T.; Perry, J.; Raine, K.; Richardson, D.; Shepherd, R.; Small, A.; Tofts, C.; Varian, J.; Webb, T.; West, S.; Widaa, S.; Yates, A.; Cahill, D. P.; Louis, D. N.; Goldstraw, P.; Nicholson, A. G.; Brasseur, F.; Looijenga, L.; Weber, B. L.; Chiew, Y. E.; DeFazio, A.; Greaves, M. F.; Green, A. R.; Campbell, P.; Birney, E.; Easton, D. F.; Chenevix-Trench, G.; Tan, M. H.; Khoo, S. K.; The, B. T.; Yuen, S. T.; Leung, S. Y.; Wooster, R.; Futreal, P. A.; Stratton, M. R. Patterns of somatic mutation in human cancer genomes. Nature, 2007, 446(7132), 153-158.
114. Nannini, M.; Pantaleo, M. A.; Maleddu, A.; Astolfi, A.; Formica, S.; Biasco, G. Gene expression profiling in colorectal cancer using microarray technologies: results and perspectives. Cancer Treat. Rev., 2009, 35(3), 201-209. Epub 2008 Dec. 9.
115. Van Schaeybroeck, S.; Allen, W. L.; Turkington, R. C.; Johnston, P. G. Implementing prognostic and predictive biomarkers in CRC clinical trials. Nat. Rev. Clin. Oncol., 2011, 8(4), 222-232.
116. Arango, D.; Wilson, A. J.; Shi, Q.; Corner, G. A.; Arañes, M. J.; Nicholas, C.; Lesser, M.; Mariadason, J. M.; Augenlicht, L. H. D. Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells. B r. J. Cancer, 2004, 91, 1931-1946.
117. Khambata-Ford, S.; Garrett, C. R.; Meropol, N. J.; Basik, M.; Harbison, C. T.; Wu, S.; Wong, T. W.; Huang, X.; Takimoto, C. H.; Godwin, A. K.; Tan, B. R.; Krishnamurthi, S. S.; Burris, H. A. 3rd; Poplin, E. A.; Hidalgo, M.; Baselga, J.; Clark, E. A.; Mauro, D. J. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol., 2007, 25, 3230-3237.
118. Ghadimi, B. M.; Grade, M.; Difilippantonio, M. J.; Varma, S.; Simon, R.; Montagna, C.; Füzesi, L.; Langer, C.; Becker, H.; Liersch, T.; Ried, T. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J. Clin. Oncol., 2005, 23, 1826-1838.
119. Kim, I. J.; Lim, S. B.; Kang, H. C.; Chang, H. J.; Ahn, S. A.; Park, H. W.; Jang, S. G.; Park, J. H.; Kim, D. Y.; Jung, K. H.; Choi, H. S.; Jeong, S. Y.; Sohn, D. K.; Kim, D. W.; Park, J. G. Microarray gene expression profiling for predicting complete response to preoperative chemoradiotherapy in patients with advanced rectal cancer. Dis. Colon Rectum, 2007, 50, 1342-1353.
120. Rimkus, C.; Friederichs, J.; Boulesteix, A. L.; Theisen, J.; Mages, J.; Becker, K.; Nekarda, H.; Rosenberg, R.; Janssen, K. P.; Siewert, J. R. Microarraybased prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal cancer. Clin. Gastroenterol. Hepatol., 2008, 6, 53-61.
121. MAQC Consortium, Shi, L.; Reid, L. H.; Jones, W. D.; Shippy, R.; Warrington, J. A.; Baker, S. C.; Collins, P. J.; de Longueville, F.; Kawasaki, E. S.; Lee, K. Y.; Luo, Y.; Sun, Y. A.; Willey, J. C.; Setterquist, R. A.; Fischer, G. M., Tong, W.; Dragan, Y. P.; Dix, D. J.; Frueh, F. W.; Goodsaid, F. M.; Herman, D.; Jensen, R. V.; Johnson, C. D.; Lobenhofer, E. K.; Puri, R. K.; Scherf, U.; Thierry-Mieg, J.; Wang, C.; Wilson, M.; Wolber, P. K.; Zhang, L.; Amur, S.; Bao, W.; Barbacioru, C. C.; Lucas, A. B.; Bertholet, V.; Boysen, C.; Bromley, B.; Brown, D.; Brunner, A.; Canales, R.; Cao, X. M.; Cebula, T. A.; Chen, J. J.; Cheng, J.; Chu, T. M.; Chudin, E.; Corson, J.; Corton, J. C.; Croner, L. J.; Davies, C.; Davison, T. S.; Delenstarr, G.; Deng, X.; Dorris, D.; Eklund, A. C.; Fan, X. H.; Fang, H.; Fulmer-Smentek, S.; Fuscoe, J. C.; Gallagher, K.; Ge, W.; Guo, L.; Guo, X.; Hager, J.; Haje, P. K.; Han, J.; Han, T.; Harbottle, H. C.; Harris, S. C.; Hatchwell, E.; Hauser, C. A.; Hester, S.; Hong, H.; Hurban, P.; Jackson, S. A.; Ji, H.; Knight, C. R.; Kuo, W. P.; LeClerc, J. E.; Levy, S.; Li, Q. Z.; Liu, C.; Liu, Y.; Lombardi, M. J.; Ma, Y.; Magnuson, S. R.; Maqsodi, B.; McDaniel, T.; Mei, N.; Myklebost, O.; Ning, B.; Novoradovskaya, N.; Orr, M. S.; Osborn, T. W.; Papallo, A.; Patterson, T. A.; Perkins, R. G.; Peters, E. H.; Peterson, R.; Philips, K. L.; Pine, P. S.; Pusztai, L.; Qian, F.; Ren, H.; Rosen, M.; Rosenzweig, B. A.; Samaha, R. R.; Schena, M.; Schroth, G. P.; Shchegrova, S.; Smith, D. D.; Staedtler, F.; Su, Z.; Sun, H.; Szallasi, Z.; Tezak, Z.; Thierry-Mieg, D.; Thompson, K. L.; Tikhonova, I.; Turpaz, Y.; Vallanat, B.; Van, C.; Walker, S. J.; Wang, S. J.; Wang, Y.; Wolfinger, R.; Wong, A.; Wu, J.; Xiao, C.; Xie, Q.; Xu, J.; Yang, W.; Zhang, L.; Zhong, S.; Zong, Y.; Slikker, W. Jr. The MicroArray Quality Control (MAQC) project shows inter-and intraplatform reproducibility of gene expression measurements. Nat. Biotechnol., 2006, 24(9), 1151-1161.
122. Timmermann, B.; Kerick, M.; Roehr, C.; Fischer, A.; Isau, M.; Boerno, S. T.; Wunderlich, A.; Barmeyer, C.; Seemann, P.; Koenig, J.; Lappe, M.; Kuss, A. W.; Garshasbi, M.; Bertram, L.; Trappe, K.; Werber, M.; Herrmann, B. G.; Zatloukal, K.; Lehrach, H.; Schweiger, M. R. Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis. PLoS One, 2010, 5(12), e15661.
123. Cronin, M.; Ross, J. S. Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. Biomark. Med., 2011, 5(3):293-305.
124. Araujo, R. P.; Petricoin, E. F.; Liotta, L. A. A mathematical model of combination therapy using the EGFR signaling network. Biosystems, 2005, 80(1), 57-69.
125. Araujo, R.; Doran, C.; Liotta, L. A.; Petricoin, E. F. Network targeted combination therapy: a new concept in cancer treatment. Drug Discov. Today, 2004, 1, 425-433.
126. Del Rio, M.; Molina, F.; Bascoul-Mollevi, C.; Copois, V.; Bibeau, F.; Chalbos, P.; Bareil, C.; Kramar, A.; Salvetat, N.; Fraslon, C.; Conseiller, E.; Granci, V.; Leblanc, B.; Pau, B.; Martineau, P.; Ychou, M. M. Gene expression signature in advanced colorectal cancer patients select drugs and response for the use of leucovorin, fluorouracil, and irinotecan. J. Clin. Oncol., 2007, 25, 773-780.
127. Dancey, J. E.; Chen, H. X. Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat. Rev. Drug Discov., 2006, 5(8), 649-659.
128. Paraiso, K. H.; Fedorenko, I. V.; Cantini, L. P.; Munko, A. C.; Hall, M.; Sondak, V. K.; Messina, J. L.; Flaherty, K. T.; Smalley, K. S. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. B r. J. Cancer, 2010, 102(12), 1724-30.
129. Johannessen, C. M.; Boehm, J. S.; Kim, S. Y.; Thomas, S. R.; Wardwell, L.; Johnson, L. A.; Emery, C. M.; Stransky, N.; Cogdill, A. P.; Barretina, J.; Caponigro, G.; Hieronymus, H.; Murray, R. R.; Salehi-Ashtiani, K.; Hill, D. E.; Vidal, M.; Zhao, J. J.; Yang, X.; Alkan, O.; Kim, S.; Harris, J. L.; Wilson, C. J.; Myer, V. E.; Finan, P. M.; Root, D. E.; Roberts, T. M.; Golub, T.; Flaherty, K. T.; Dummer, R.; Weber, B. L.; Sellers, W. R.; Schlegel, R.; Wargo, J. A.; Hahn, W. C.; Garraway, L. A. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 2010, 468(7326), 968-972. Epub 2010 Nov. 24.
130. Smalley, K. S.; Haass, N. K.; Brafford, P. A.; Lioni, M.; Flaherty, K. T.; Herlyn, M. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol. Cancer Ther., 2006, 5(5), 1136-1144.
131. Lasithiotakis, K. G.; Sinnberg, T. W.; Schittek, B.; Flaherty, K. T.; Kulms, D.; Maczey, E.; Garbe, C.; Meier, F. E. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J. Invest. Dermatol., 2008, 128(8), 2013-2023. Epub 2008 Mar. 6.
132. Holt, S. V.; Logie, A.; Davies, B. R.; Alferez, D.; Runswick, S.; Fenton, S.; Chresta, C. M.; Gu, Y.; Zhang, J.; Wu, Y. L.; Wilkinson, R. W.; Guichard, S.; Smith, P. D. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK and mTOR kinase inhibitors. Cancer Res., 2012, Jan 23. [Epub ahead of print]
133. Yang, H.; Higgins, B.; Kolinsky, K.; Packman, K.; Bradley, W. D.; Lee, R. J.; Schostack, K.; Simcox, M. E.; Kopetz, S.; Heimbrook, D.; Lestini, B.; Bollag, G.; Su, F. Antitumor Activity of BRAF Inhibitor Vemurafenib in Preclinical Models of BRAF-Mutant Colorectal Cancer. Cancer Res., 2012, 72(3), 779-789.
134. Newman, D. J.; Cragg, G. M. Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010. J. Nat. Prod., 2012, Feb. 8. [Epub ahead of print]
135. Goldie, J. H.; Coldman, A. J. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat. Rep., 1979, 63(11-12), 1727-1733.
136. Pierotti, M. A.; Tamborini, E.; Negri, T.; Pricl, S.; Pilotti, S. Targeted therapy in GIST: in silico modeling for prediction of resistance. Nat. Rev. Clin. Oncol., 2011, 8(3), 161-170.
137. Swierniak, A.; Kimmel, M.; Smieja, J. Mathematical modeling as a tool for planning anticancer therapy. Eur. J. Pharmacol., 2009, 625(1-3), 108-121.