Using small molecules and chemical genetics to interrogate signaling networks

ACS Chemical Biology

Volumn 6, Issue 1, 2011, Pages 75-85

  Carlson, Scott M ^a   White, Forest M ^a  

^a Massachusetts Institute of Technology Cambridge   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DASATINIB; GEFITINIB; IMATINIB; 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; PHOSPHOTRANSFERASE INHIBITOR; RAPAMYCIN; UO 126; WORTMANNIN;

CANCER CELL; CANCER REGRESSION; CANCER SURVIVAL; CANCER THERAPY; CHEMICAL GENETICS; DOWNSTREAM PROCESSING; DRUG TARGETING; FEEDBACK SYSTEM; HUMAN; MOLECULAR LIBRARY; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEOMICS; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

DRUG DELIVERY SYSTEMS; MOLECULAR BIOLOGY; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEOMICS; SIGNAL TRANSDUCTION; SMALL MOLECULE LIBRARIES;

EID: 79251513964     PISSN: 15548929     EISSN: 15548937     Source Type: Journal    
DOI: 10.1021/cb1002834     Document Type: Review

References (90)

1. Hanahan, D. and Weinberg, R. (2000) The hallmarks of cancer Cell 100, 57-70
2. Vang, T., Miletic, A., Arimura, Y., Tautz, L., Rickert, R., and Mustelin, T. (2008) Protein tyrosine phosphatases in autoimmunity Annu. Rev. Immunol. 26, 29-55
3. Froüjdoü, S., Vidal, H., and Pirola, L. (2009) Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans Biochim. Biophys. Acta 1792, 83-92
4. Karess, R., Hayward, W., and Hanafusa, H. (1979) Cellular information in the genome of recovered avian sarcoma virus directs the synthesis of transforming protein Proc. Natl. Acad. Sci. U.S.A. 76, 3154-3158 (Pubitemid 9233249)
5. Daley, G., Van Etten, R., and Baltimore, D. (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome Science 247, 824-830
6. Aaronson, S. (1991) Growth factors and cancer Science 254, 1146-1153
7. Zhang, J., Yang, P., and Gray, N. (2009) Targeting cancer with small molecule kinase inhibitors Nat. Rev. Cancer 9, 28-39
8. Janes, K., Albeck, J., Peng, L., Sorger, P., Lauffenburger, D., and Yaffe, M. (2003) A high-throughput quantitative multiplex kinase assay for monitoring information flow in signaling networks: application to sepsis-apoptosis Mol. Cell. Proteomics 2, 463-473
9. Krutzik, P., Crane, J., Clutter, M., and Nolan, G. (2008) High-content single-cell drug screening with phosphospecific flow cytometry Nat. Chem. Biol. 4, 132-142
10. Ciaccio, M., Wagner, J., Chuu, C., Lauffenburger, D., and Jones, R. (2010) Systems analysis of EGF receptor signaling dynamics with microwestern arrays Nat. Methods 7, 148-155
11. Schmelzle, K. and White, F. (2006) Phosphoproteomic approaches to elucidate cellular signaling networks Curr. Opin. Biotechnol. 17, 406-414
12. Choudhary, C. and Mann, M. (2010) Decoding signalling networks by mass spectrometry-based proteomics Nat. Rev. Mol. Cell. Biol. 11, 427-439
13. Grimsrud, P., Swaney, D., Wenger, C., Beauchene, N., and Coon, J. (2010) Phosphoproteomics for the masses ACS Chem. Biol. 5, 105-119
14. Faratian, D., Goltsov, A., Lebedeva, G., Sorokin, A., Moodie, S., Mullen, P., Kay, C., Um, I., Langdon, S., Goryanin, I., and Harrison, D. (2009) Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab Cancer Res. 69, 6713-6720
15. Brehmer, D., Godl, K., Zech, B., Wissing, J., and Daub, H. (2004) Proteome-wide identification of cellular targets affected by bisindolylmaleimide-type protein kinase C inhibitors Mol. Cell. Proteomics 3, 490-500
16. Fabian, M., Biggs, W. r., Treiber, D., Atteridge, C., Azimioara, M., Benedetti, M., Carter, T., Ciceri, P., Edeen, P., Floyd, M., Ford, J., Galvin, M., Gerlach, J., Grotzfeld, R., Herrgard, S., Insko, D., Insko, M., Lai, A., Lelias, J., Mehta, S., Milanov, Z., Velasco, A., Wodicka, L., Patel, H., Zarrinkar, P., and Lockhart, D. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors Nat. Biotechnol. 23, 329-336
17. Lamb, J., Crawford, E., Peck, D., Modell, J., Blat, I., Wrobel, M., Lerner, J., Brunet, J., Subramanian, A., Ross, K., Reich, M., Hieronymus, H., Wei, G., Armstrong, S., Haggarty, S., Clemons, P., Wei, R., Carr, S., Lander, E., and Golub, T. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease Science 313, 1929-1935
18. Rix, U. and Superti-Furga, G. (2009) Target profiling of small molecules by chemical proteomics Nat. Chem. Biol. 5, 616-624
19. Heidorn, S., Milagre, C., Whittaker, S., Nourry, A., Niculescu-Duvas, I., Dhomen, N., Hussain, J., Reis-Filho, J., Springer, C., Pritchard, C., and Marais, R. (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF Cell 140, 209-221
20. Alexopoulos, L., Saez-Rodriguez, J., Cosgrove, B., Lauffenburger, D., and Sorger, P. (2010) Networks inferred from biochemical data reveal profound differences in Toll-like receptor and inflammatory signaling between normal and transformed hepatocytes Mol. Cell. Proteomics 9, 1849-1865
21. Janes, K., Albeck, J., Gaudet, S., Sorger, P., Lauffenburger, D., and Yaffe, M. (2005) A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis Science 310, 1646-1653
22. Irish, J., Kotecha, N., and Nolan, G. (2006) Mapping normal and cancer cell signalling networks: towards single-cell proteomics Nat. Rev. Cancer 6, 146-155
23. Chan, S., Ermann, J., Su, L., Fathman, C., and Utz, P. (2004) Protein microarrays for multiplex analysis of signal transduction pathways Nat. Med. 10, 1390-1396
24. Wolf-Yadlin, A., Sevecka, M., and MacBeath, G. (2009) Dissecting protein function and signaling using protein microarrays Curr. Opin. Chem. Biol. 13, 398-405
25. Sevecka, M. and MacBeath, G. (2006) State-based discovery: a multidimensional screen for small-molecule modulators of EGF signaling Nat. Methods 3, 825-831
26. Ficarro, S. B., McCleland, M. L., Stukenberg, P. T., Burke, D. J., Ross, M. M., Shabanowitz, J., Hunt, D. F., and White, F. M. (2002) Phosphoproteome analysis by mass spectrometry and its application to Saccharomyces cerevisiae Nat. Biotechnol. 20, 301-305
27. Beausoleil, S., Jedrychowski, M., Schwartz, D., Elias, J., Villén, J., Li, J., Cohn, M., Cantley, L., and Gygi, S. (2004) Large-scale characterization of HeLa cell nuclear phosphoproteins Proc. Natl. Acad. Sci. U.S.A. 101, 12130-12135
28. Larsen, M., Thingholm, T., Jensen, O., Roepstorff, P., and Jørgensen, T. (2005) Highly selective enrichment of phosphorylated peptides from peptide mixtures using titanium dioxide microcolumns Mol. Cell. Proteomics 4, 873-886
29. Ong, S. and Mann, M. (2006) Identifying and quantifying sites of protein methylation by heavy methyl SILAC, Curr. Protoc. Protein Sci. Chapter 14, Unit 14.19.
30. Kim, S., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., Grishin, N., White, M., Yang, X., and Zhao, Y. (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey Mol. Cell 23, 607-618
31. Choudhary, C., Kumar, C., Gnad, F., Nielsen, M., Rehman, M., Walther, T., Olsen, J., and Mann, M. (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions Science 325, 834-840
32. Xu, G., Paige, J., and Jaffrey, S. (2010) Global analysis of lysine ubiquitination by ubiquitin remnant immunoaffinity profiling Nat. Biotechnol. 28, 868-873
33. Peng, J., Schwartz, D., Elias, J., Thoreen, C., Cheng, D., Marsischky, G., Roelofs, J., Finley, D., and Gygi, S. (2003) A proteomics approach to understanding protein ubiquitination Nat. Biotechnol. 21, 921-926
34. Paige, J., Xu, G., Stancevic, B., and Jaffrey, S. (2008) Nitrosothiol reactivity profiling identifies S-nitrosylated proteins with unexpected stability Chem. Biol. 15, 1307-1316
35. Tannenbaum, S. and White, F. (2006) Regulation and specificity of S-nitrosylation and denitrosylation ACS Chem. Biol. 1, 615-618
36. Moser, K. and White, F. (2006) Phosphoproteomic analysis of rat liver by high capacity IMAC and LC-MS/MS J. Proteome Res. 5, 98-104
37. Olsen, J., Blagoev, B., Gnad, F., Macek, B., Kumar, C., Mortensen, P., and Mann, M. (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks Cell 127, 635-648
38. Dephoure, N., Zhou, C., Villén, J., Beausoleil, S., Bakalarski, C., Elledge, S., and Gygi, S. (2008) A quantitative atlas of mitotic phosphorylation Proc. Natl. Acad. Sci. U.S.A. 105, 10762-10767
39. Macek, B., Mann, M., and Olsen, J. (2009) Global and site-specific quantitative phosphoproteomics: principles and applications Annu. Rev. Pharmacol. Toxicol. 49, 199-221
40. Pan, C., Olsen, J., Daub, H., and Mann, M. (2009) Global effects of kinase inhibitors on signaling networks revealed by quantitative phosphoproteomics Mol. Cell. Proteomics 8, 2796-2808
41. Hunter, T. and Sefton, B. (1980) Transforming gene product of Rous sarcoma virus phosphorylates tyrosine Proc. Natl. Acad. Sci. U.S.A. 77, 1311-1315
42. Rush, J., Moritz, A., Lee, K., Guo, A., Goss, V., Spek, E., Zhang, H., Zha, X., Polakiewicz, R., and Comb, M. (2005) Immunoaffinity profiling of tyrosine phosphorylation in cancer cells Nat. Biotechnol. 23, 94-101
43. Zhang, Y., Wolf-Yadlin, A., Ross, P., Pappin, D., Rush, J., Lauffenburger, D., and White, F. (2005) Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules Mol. Cell. Proteomics 4, 1240-1250
44. Haystead, C., Gregory, P., Sturgill, T., and Haystead, T. (1993) Gamma-phosphate-linked ATP-sepharose for the affinity purification of protein kinases. Rapid purification to homogeneity of skeletal muscle mitogen-activated protein kinase kinase Eur. J. Biochem. 214, 459-467
45. Li, J., Rix, U., Fang, B., Bai, Y., Edwards, A., Colinge, J., Bennett, K., Gao, J., Song, L., Eschrich, S., Superti-Furga, G., Koomen, J., and Haura, E. (2010) A chemical and phosphoproteomic characterization of dasatinib action in lung cancer Nat. Chem. Biol. 6, 291-299
46. Moritz, A., Li, Y., Guo, A., Villén, J., Wang, Y., MacNeill, J., Kornhauser, J., Sprott, K., Zhou, J., Possemato, A., Ren, J., Hornbeck, P., Cantley, L., Gygi, S., Rush, J., and Comb, M. (2010) Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases Sci Signal 3, ra64
47. Andersen, J., Sathyanarayanan, S., Di Bacco, A., Chi, A., Zhang, T., Chen, A., Dolinski, B., Kraus, M., Roberts, B., Arthur, W., Klinghoffer, R., Gargano, D., Li, L., Feldman, I., Lynch, B., Rush, J., Hendrickson, R., Blume-Jensen, P., and Paweletz, C. (2010) Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors Sci. Transl. Med. 2 43ra55
48. Ong, S., Blagoev, B., Kratchmarova, I., Kristensen, D., Steen, H., Pandey, A., and Mann, M. (2002) Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics Mol. Cell. Proteomics 1, 376-386
49. Ross, P., Huang, Y., Marchese, J., Williamson, B., Parker, K., Hattan, S., Khainovski, N., Pillai, S., Dey, S., Daniels, S., Purkayastha, S., Juhasz, P., Martin, S., Bartlet-Jones, M., He, F., Jacobson, A., and Pappin, D. (2004) Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents Mol. Cell. Proteomics 3, 1154-1169
50. Huang, P., Mukasa, A., Bonavia, R., Flynn, R., Brewer, Z., Cavenee, W., Furnari, F., and White, F. (2007) Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma Proc. Natl. Acad. Sci. U.S.A. 104, 12867-12872
51. Guo, A., Villén, J., Kornhauser, J., Lee, K., Stokes, M., Rikova, K., Possemato, A., Nardone, J., Innocenti, G., Wetzel, R., Wang, Y., MacNeill, J., Mitchell, J., Gygi, S., Rush, J., Polakiewicz, R., and Comb, M. (2008) Signaling networks assembled by oncogenic EGFR and c-Met Proc. Natl. Acad. Sci. U.S.A. 105, 692-697
52. Engelman, J., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J., Lindeman, N., Gale, C., Zhao, X., Christensen, J., Kosaka, T., Holmes, A., Rogers, A., Cappuzzo, F., Mok, T., Lee, C., Johnson, B., Cantley, L., and Jaünne, P. (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling Science 316, 1039-1043
53. Goss, V., Lee, K., Moritz, A., Nardone, J., Spek, E., MacNeill, J., Rush, J., Comb, M., and Polakiewicz, R. (2006) A common phosphotyrosine signature for the Bcr-Abl kinase Blood 107, 4888-4897
54. Yan, G., Xiao, C., He, G., Yin, X., Chen, N., Cao, Y., and He, Q. (2010) Global phosphoproteomic effects of natural tyrosine kinase inhibitor, genistein, on signaling pathways Proteomics 10, 976-986
55. Oyama, M., Kozuka-Hata, H., Tasaki, S., Semba, K., Hattori, S., Sugano, S., Inoue, J., and Yamamoto, T. (2009) Temporal perturbation of tyrosine phosphoproteome dynamics reveals the system-wide regulatory networks Mol. Cell. Proteomics 8, 226-231
56. Lienhard, G. (2008) Non-functional phosphorylations? Trends Biochem. Sci. 33, 351-352
57. Olsen, J., Vermeulen, M., Santamaria, A., Kumar, C., Miller, M., Jensen, L., Gnad, F., Cox, J., Jensen, T., Nigg, E., Brunak, S., and Mann, M. (2010) Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis Sci. Signal. 3, ra3
58. Janes, K. and Lauffenburger, D. (2006) A biological approach to computational models of proteomic networks Curr. Opin. Chem. Biol. 10, 73-80
59. Kumar, N., Wolf-Yadlin, A., White, F., and Lauffenburger, D. (2007) Modeling HER2 effects on cell behavior from mass spectrometry phosphotyrosine data PLoS Comput. Biol. 3 e4
60. Chen, W., Schoeberl, B., Jasper, P., Niepel, M., Nielsen, U., Lauffenburger, D., and Sorger, P. (2009) Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data Mol. Syst. Biol. 5, 239
61. Schoeberl, B., Pace, E., Fitzgerald, J., Harms, B., Xu, L., Nie, L., Linggi, B., Kalra, A., Paragas, V., Bukhalid, R., Grantcharova, V., Kohli, N., West, K., Leszczyniecka, M., Feldhaus, M., Kudla, A., and Nielsen, U. (2009) Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis Sci. Signal. 2, ra31
62. Sopko, R. and Andrews, B. (2008) Linking the kinome and phosphorylomeéa comprehensive review of approaches to find kinase targets Mol. Biosyst. 4, 920-933
63. Blair, J., Rauh, D., Kung, C., Yun, C., Fan, Q., Rode, H., Zhang, C., Eck, M., Weiss, W., and Shokat, K. (2007) Structure-guided development of affinity probes for tyrosine kinases using chemical genetics Nat. Chem. Biol. 3, 229-238
64. Maly, D., Allen, J., and Shokat, K. (2004) A mechanism-based cross-linker for the identification of kinase-substrate pairs J. Am. Chem. Soc. 126, 9160-9161
65. Shah, K., Liu, Y., Deirmengian, C., and Shokat, K. (1997) Engineering unnatural nucleotide specificity for Rous sarcoma virus tyrosine kinase to uniquely label its direct substrates Proc. Natl. Acad. Sci. U.S.A. 94, 3565-3570
66. Bishop, A., Shah, K., Liu, Y., Witucki, L., Kung, C., and Shokat, K. (1998) Design of allele-specific inhibitors to probe protein kinase signaling Curr. Biol. 8, 257-266
67. Liu, Y., Shah, K., Yang, F., Witucki, L., and Shokat, K. (1998) Engineering Src family protein kinases with unnatural nucleotide specificity Chem. Biol. 5, 91-101
68. Ventura, J., Huübner, A., Zhang, C., Flavell, R., Shokat, K., and Davis, R. (2006) Chemical genetic analysis of the time course of signal transduction by JNK Mol. Cell 21, 701-710
69. Das, M., Jiang, F., Sluss, H., Zhang, C., Shokat, K., Flavell, R., and Davis, R. (2007) Suppression of p53-dependent senescence by the JNK signal transduction pathway Proc. Natl. Acad. Sci. U.S.A. 104, 15759-15764
70. Burkard, M., Randall, C., Larochelle, S., Zhang, C., Shokat, K., Fisher, R., and Jallepalli, P. (2007) Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells Proc. Natl. Acad. Sci. U.S.A. 104, 4383-4388
71. Shah, K. and Shokat, K. (2002) A chemical genetic screen for direct v-Src substrates reveals ordered assembly of a retrograde signaling pathway Chem. Biol. 9, 35-47
72. Habelhah, H., Shah, K., Huang, L., Burlingame, A., Shokat, K., and Ronai, Z. (2001) Identification of new JNK substrate using ATP pocket mutant JNK and a corresponding ATP analogue J. Biol. Chem. 276, 18090-18095
73. Niswender, C., Ishihara, R., Judge, L., Zhang, C., Shokat, K., and McKnight, G. (2002) Protein engineering of protein kinase A catalytic subunits results in the acquisition of novel inhibitor sensitivity J. Biol. Chem. 277, 28916-28922
74. Ubersax, J., Woodbury, E., Quang, P., Paraz, M., Blethrow, J., Shah, K., Shokat, K., and Morgan, D. (2003) Targets of the cyclin-dependent kinase Cdk1 Nature 425, 859-864
75. Eblen, S., Kumar, N., Shah, K., Henderson, M., Watts, C., Shokat, K., and Weber, M. (2003) Identification of novel ERK2 substrates through use of an engineered kinase and ATP analogs J. Biol. Chem. 278, 14926-14935
76. Blethrow, J., Zhang, C., Shokat, K., and Weiss, E. (2004) Design and use of analog-sensitive protein kinases, Curr. Protoc. Mol. Biol. Chapter 18, Unit 18.11.
77. Allen, J., Lazerwith, S., and Shokat, K. (2005) Bio-orthogonal affinity purification of direct kinase substrates J. Am. Chem. Soc. 127, 5288-5289
78. Allen, J., Li, M., Brinkworth, C., Paulson, J., Wang, D., Huübner, A., Chou, W., Davis, R., Burlingame, A., Messing, R., Katayama, C., Hedrick, S., and Shokat, K. (2007) A semisynthetic epitope for kinase substrates Nat. Methods 4, 511-516
79. Blethrow, J., Glavy, J., Morgan, D., and Shokat, K. (2008) Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates Proc. Natl. Acad. Sci. U.S.A. 105, 1442-1447
80. Chi, Y., Welcker, M., Hizli, A. A., Posakony, J. J., Aebersold, R., and Clurman, B. E. (2008) Identification of CDK2 substrates in human cell lysates Genome Biol. 9, R149
81. Apperley, J. (2007) Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia Lancet Oncol. 8, 1018-1029
82. Kobayashi, S., Boggon, T., Dayaram, T., Jaünne, P., Kocher, O., Meyerson, M., Johnson, B., Eck, M., Tenen, D., and Halmos, B. (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib N. Engl. J. Med. 352, 786-792
83. Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B., Anderson, D., Alvarado, R., Ludlam, M., Stokoe, D., Gloor, S., Vigers, G., Morales, T., Aliagas, I., Liu, B., Sideris, S., Hoeflich, K., Jaiswal, B., Seshagiri, S., Koeppen, H., Belvin, M., Friedman, L., and Malek, S. (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth Nature 464, 431-435
84. Poulikakos, P., Zhang, C., Bollag, G., Shokat, K., and Rosen, N. (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF Nature 464, 427-430
85. Sathornsumetee, S., Reardon, D., Desjardins, A., Quinn, J., Vredenburgh, J., and Rich, J. (2007) Molecularly targeted therapy for malignant glioma Cancer 110, 13-24
86. Mellinghoff, I., Wang, M., Vivanco, I., Haas-Kogan, D., Zhu, S., Dia, E., Lu, K., Yoshimoto, K., Huang, J., Chute, D., Riggs, B., Horvath, S., Liau, L., Cavenee, W., Rao, P., Beroukhim, R., Peck, T., Lee, J., Sellers, W., Stokoe, D., Prados, M., Cloughesy, T., Sawyers, C., and Mischel, P. (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors N. Engl. J. Med. 353, 2012-2024
87. Wang, M., Lu, K., Zhu, S., Dia, E., Vivanco, I., Shackleford, G., Cavenee, W., Mellinghoff, I., Cloughesy, T., Sawyers, C., and Mischel, P. (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells Cancer Res. 66, 7864-7869
88. Akhavan, D., Cloughesy, T., and Mischel, P. (2010) mTOR signaling in glioblastoma: lessons learned from bench to bedside Neuro-Oncology 12, 882-889
89. Gray-Schopfer, V., Wellbrock, C., and Marais, R. (2007) Melanoma biology and new targeted therapy Nature 445, 851-857
90. Gazdar, A. (2009) Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors Oncogene 28 (Suppl 1) S24-31