Targeting the Raf kinase cascade in cancer therapy - Novel molecular targets and therapeutic strategies

Expert Opinion on Therapeutic Targets

Volumn 6, Issue 6, 2002, Pages 659-678

  Lee Jr , John T ^a   McCubrey, James A ^a  

^a EAST CAROLINA UNIVERSITY   (United States)

Author keywords

Akt; Chemotherapy; Drug resistance; Epidermal growth factor (EGF); Extracellular signal regulated kinase (ERK); Inhibitors; Janus family of kinases (JAK); MAPK kinase (MEK); Mitogen activated protein kinase (MAPK); Oncogenes; Phosphatidylinositol 3 kinase C (P13K); Platelet derived growth factor (PDGF); Protein kinase C (PKC); Raf; Ras; Signal transduction

Indexed keywords

2 (2 AMINO 3 METHOXYPHENYL)CHROMONE; 2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; 2 [1 (3 AMIDINOTHIOPROPYL) 1H INDOL 3 YL] 3 (1 METHYL 1H INDOL 3 YL)MALEIMIDE; 2 [1 (3 DIMETHYLAMINOPROPYL) 3 INDOLYL] 3 (3 INDOLYL)MALEIMIDE; 3 BENZYL 7 CYANO 2,3,4,5 TETRAHYDRO 1 (1H IMIDAZOL 4 YLMETHYL) 4 (2 THIENYLSULFONYL) 1H 1,4 BENZODIAZEPINE; 4 (3 BROMOANILINO) 6,7 DIMETHOXYQUINAZOLINE; 4 (4 HYDROXYANILINO) 6,7 DIMETHOXYQUINAZOLINE; 6,7 DIMETHYL 2 PHENYLQUINOXALINE; 7 HYDROXYSTAUROSPORINE; APTAMER; CGP 69846A; ERLOTINIB; GEFITINIB; GELDANAMYCIN; IMATINIB; ISIS 3521; L 778123; LONAFARNIB; MITOGEN ACTIVATED PROTEIN KINASE; N [4 METHYL 3 [4 (3 PYRIDINYL) 2 PYRIMIDINYLAMINO]PHENYL]BENZAMIDE; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; NOVOBIOCIN; NUCLEIC ACID; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN KINASE; RAF PROTEIN; STAUROSPORINE; TIPIFARNIB; UNINDEXED DRUG; UO 126;

CANCER CHEMOTHERAPY; CARCINOGENESIS; CELL TYPE; COMPETITIVE INHIBITION; DRUG DESIGN; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVATION; ENZYME INHIBITION; MOLECULAR BIOLOGY; PROTEIN FAMILY; REVIEW; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; CELL DIVISION; CYTOKINES; DRUG DESIGN; DRUG SYNERGISM; HUMANS; MAP KINASE SIGNALING SYSTEM; MOLECULAR STRUCTURE; NEOPLASMS; ONCOGENE PROTEINS; PROTEIN KINASE INHIBITORS; PROTEIN PROCESSING, POST-TRANSLATIONAL; RAF KINASES; RECEPTORS, GROWTH FACTOR; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 0036931949     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.6.6.659     Document Type: Review

References (113)

1. BOULTON TG, NYE SH, ROBBINS DJ et al.: ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell (1991) 65(4):663-675.
2. CREWS CM, ALESSANDRINI A, ERIKSON RL: The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science (1992) 258(5081):478-480.
3. KYRIAKIS JM, APP H, ZHANG XF et al.: Raf-1 activates MAP kinase-kinase. Nature (1992) 358(6385):417-421.
4. JOHNSTON SR: Farnesyl transferase inhibitors: a novel targeted therapy for cancer. Lancet Oncol. (2001) 2(1):18-26.
5. NEW L, HAN J: The p38 MAP kinase pathway and its biological function. Trends Cardiovasc. Med. (1998) 8(5):220-228.
6. ENSLEN H, BRANCHO DM, DAVIS RJ: Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J. (2000) 19(6):1301-1311.
7. OBATA T, BROWN GE, YAFFE MB: MAP kinase pathways activated by stress: the p38 MAPK pathway. Crit. Care Med. (2000) 28(4 Suppl.):N67-N77.
8. SANCHEZ I, HUGHES RT, MAYER BJ et al.: Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature (1994) 372(6508):794-798.
9. ICHIJO H: From receptors to stress-activated MAP kinases. Oncogene (1999) 18(45):6087-6093.
10. KOLCH W: Ras/Raf signalling and emerging pharmacotherapeutic targets. Expert Opin. Pharmacother. (2002) 3(6):709-718.
11. YARDEN Y: The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur. J. Cancer (2001) 37(Suppl. 4):S3-S8.
12. WEINSTEIN-OPPENHEIMER CR, BLALOCK WL, STEELMAN LS, CHANG F, MCCUBREY JA: The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors. Pharmacol. Ther. (2000) 88(3):229-279.
13. BOWERS G, REARDON D, HEWITT T et al.: The relative role of ErbB1-4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells. Oncogene (2001) 20(11):1388-1397.
14. HELDIN CH, WESTERMARK B: Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. (1999) 79(4):1283-1316.
15. BERGSTEN E, UUTELA M, LI X et al.: PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat. Cell. Biol. (2001) 3(5):512-516.
16. BLALOCK WL, WEINSTEIN-OPPENHEIMER C, CHANG F et al.: Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs. Leukemia (1999) 13(8):1109-1166.
17. ROSS EM, WILKIE TM: GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Ann. Rev. Biochem. (2000) 69:795-827.
18. IHLE JN, WITTHUHN BA, QUELLE FW et al.: Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem. Sci. (1994) 19(5):222-227.
19. STANCATO LF, YU CR, PETRICOIN EF III, LARNER AC: Activation of Raf-1 by interferon gamma and oncostatin M requires expression of the Stat1 transcription factor. J. Biol. Chem. (1998) 273(30):18701-18704.
20. HO JM, NGUYEN MH, DIEROV JK et al.: TEL-JAK-2 constitutively activates the extracellular signal-regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways. Blood (2002) 100(4):1438-1448.
21. HAGEMANN C, RAPP UR: Isotype-specific functions of Raf kinases. Exp. Cell Res. (1999) 253(1):34-46.
22. FRANKLIN RA, MCCUBREY JA: Kinases: positive and negative regulators of apoptosis. Leukemia (2000) 14(12):2019-2034.
23. WHITE MK, MCCUBREY JA: Suppression of apoptosis: role in cell growth and neoplasia. Leukemia (2001) 15(7):1011-1021.
24. SEWING A, WISEMAN B, LLOYD AC, LAND H: High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol. Cell. Biol. (1997) 17(9):5588-5597.
25. DAVIES SP, REDDY H, CAIVANO M, COHEN P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. (2000) 351 (Pt 1):95-105.
26. VAN AELST L, BARR M, MARCUS S, POLVERINO A, WIGLER M: Complex formation between RAS and RAF and other protein kinases. Proc. Natl. Acad. Sci. USA (1993) 90(13):6213-6217.
27. SOZERI O, VOLLMER K, LIYANAGE M et al.: Activation of the c-Raf protein kinase by protein kinase C phosphorylation. Oncogene (1992) 7(11):2259-2262.
28. FARRAR MA, ALBEROL-ILA, PERLMUTTER RM: Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Nature (1996) 383(6596):178-181.
29. WEBER CK, SLUPSKY JR, KALMES HA, RAPP UR: Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. (2001) 61(9):3595-3598.
30. WEBER CK, SLUPSKY JR, HERRMANN C, SCHULER M, RAPP UR, BLOCK C: Mitogenic signaling of Ras is regulated by differential interaction with Raf isozymes. Oncogene (2000) 19(2):169-176.
31. LEE JT JR, MCCUBREY JA: The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia. Leukemia (2002) 16(4):486-507.
32. MORRISON DK: KSR: a MAPK scaffold of the Ras pathway? J. Cell Sci. (2001) 114(Pt 9):1609-1612.
33. RAABE T, RAPP UR: KSR-A regulator and scaffold protein of the MAPK pathway. Sci. STKE(2002) 136:28.
34. ZHANG Y, YAO B, DELIKAT S et al.: Kinase suppressor of Ras is ceramide-activated protein kinase. Cell (1997) 89(1):63-72.
35. DA ROCHA AB, MANS DR, REGNER A, SCHWARTSMANN G: Targeting protein kinase C: new therapeutic opportunities against high-grade malignant gliomas? Oncologist (2002) 7(1):17-33.
36. SCHONWASSER DC, MARAIS RM, MARSHALL CJ, PARKER PJ: Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol. cell. Biol. (1998) 18(2):790-798.
37. UEDA Y, HIRAI S, OSADA S, SUZUKI A, MIZUNO K, OHNO S: Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf. J. Biol. Chem. (1996) 271(38):23512-23519.
38. JAFFER ZM, CHERNOFF J: p21-activated kinases: three more join the Pak. Int J. Biochem. Cell Biol. (2002) 34(7):713-717.
39. KING AJ, WIREMAN RS, HAMILTON M, MARSHALL MS: Phosphorylation site specificity of the Pak-mediated regulation of Raf-1 and cooperativity with Src. FEBS Lett. (2001) 497(1):6-14.
40. CHAUDHARY A, KING WG, MATTALIANO MD et al.: Phosphatidylinositol 3-kinase regulates Raf1 through Pak phosphorylation of serine 338. Curr. Biol. (2000) 10(9):551-554.
41. ZHENG CF, GUAN KL: Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J. Biol. Chem. (1993) 268(32):23933-23939.
42. CATLING AD, SCHAEFFER HJ, REUTER CW, REDDY GR, WEBER MJ: A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Mol. Cell. Biol. (1995) 15(10):5214-5225.
43. MANSOUR SJ, MATTEN WT, HERMANN AS et al.: Transformation of mammalian cells by constitutively active MAP kinase kinase. Science (1994) 265(5174):966-970.
44. WHITEHURST AW, WILSBACHER JL, YOU Y, LUBY-PHELPS K, MOORE MS, COBB MH: ERK-2 enters the nucleus by a carrier-independent mechanism. Proc. Natl. Acad. Sci. USA (2002) 99(11):7496-7501.
45. BRUNET A, ROUX D, LENORMAND P, DOWD S, KEYSE S, POUYSSEGUR J: Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J. (1999) 18(3):664-674.
46. TARNAWSKI AS, PAI R, WANG H, TOMIKAWA M: Translocation of MAP (Erk-1 and -2) kinases to cell nuclei and activation of c-fos gene during healing of experimental gastric ulcers. J. Physiol. Pharmacol. (1998) 49(4):479-488.
47. VANDERKUUR JA, BUTCH ER, WATERS SB, PESSIN JE, GUAN KL, CARTER-SU C: Signaling molecules involved in coupling growth hormone receptor to mitogen-activated protein kinase activation. Endocrinology (1997) 138(10):4301-4307.
48. ZHAO H, OKADA S, PESSIN JE, KORETZKY GA: Insulin receptor-mediated dissociation of Grb2 from Sos involves phosphorylation of Sos by kinase(s) other than extracellular signal-regulated kinase. J. Biol. Chem. (1998) 273(20):12061-12067.
49. IIDA M, TOWATARI M, NAKAO A et al.: Lack of constitutive activation of MAP kinase pathway in human acute myeloid leukemia cells with N-Ras mutation. Leukemia (1999) 13(4):585-589.
50. FISHER TL, BLENIS J: Evidence for two catalytically active kinase domains in pp90rsk. Mol. Cell. Biol. (1996) 16(3):1212-1219.
51. ZHAO Y, BJORBAEK C, WEREMOWICZ S, MORTON CC, MOLLER DE: RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation. Mol. Cell. Biol. (1995) 15(8):4353-4363.
52. JENSEN CJ, BUCH MB, KRAG TO, HEMMINGS BA, GAMMELTOFT S, FRODIN M: 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J. Biol. Chem. (1999) 274(38):27168-27176.
53. DROLET DW, JENISON RD, SMITH DE, PRATT D, HICKE BJ: A high throughput platform for systematic evolution of ligands by exponential enrichment (SELEX). Comb. Chem. High Throughput Screen. (1999) 2(5):271-278.
54. KIMOTO M, SHIROUZU M, MIZUTANI S et al.: Anti-(Raf-1) RNA aptamers that inhibit Ras-induced Raf-1 activation. Eur. J. Biochem. (2002) 269(2):697-704.
55. BIANCHINI M, RADRIZZANI M, BROCARDO MG et al.: Specific oligobodies against ERK-2 that recognize both the native and the denatured state of the protein. J. Immunol. Methods (2001) 252(1-2):191-197.
56. KASHLES O, YARDEN Y, FISCHER R, ULLRICH A, SCHLESSINGER J: A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization. Mol. Cell. Biol. (1991) 11(3):1454-1463.
57. LAMMERING G, VALERIE K, LIN PS et al.: Radiosensitization of malignant glioma cells through overexpression of dominant-negative epidermal growth factor receptor. Clin. Cancer Res. (2001) 7(3):682-690.
58. FEIG LA, COOPER GM: Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol. Cell. Biol. (1988) 8(8):3235-3243.
59. FIORDALISI JJ, HOLLY SP, JOHNSON RL II, PARISE LV, COX AD: A distinct class of dominant negative Ras mutants: cytosolic GTP-bound Ras effector domain mutants that inhibit Ras signaling and transformation and enhance cell adhesion. J. Biol. Chem. (2002) 277(13):10813-10823.
60. KAMPFER S, WINDEGGER M, HOCHHOLDINGER F et al.: Protein kinase C isoforms involved in the transcriptional activation of cyclin D1 by transforming Ha-Ras. J. Biol. Chem. (2001) 276(46):42834-42842.
61. HORIUCHI KY, SCHERLE PA, TRZASKOS JM, COPELAND RA: Competitive inhibition of MAP kinase activation by a peptide representing the alpha C helix of ERK. Biochemistry (1998) 37(25):8879-8885.
62. SATO JD, KAWAMOTO T, LE AD, MENDELSOHN J, POLIKOFF J, SATO GH: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol. Biol. Med. (1983) 1(5):511-529.
63. BASELGA J: The EGFR as a target for anticancer therapy - focus on cetuximab. Eur. J. Cancer (2001) 37 (Suppl. 4):S16-S22.
64. LYNCH DH, DONG-YANG X: Therapeutic potential of ABX-EGF: a fully human anti-epidermal growth factor receptor monoclonal antibody for cancer treatment. Semin. Oncol. (2002) 29 (Suppl. 4):47-50.
65. HERBST RS, SHIN DM: Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer (2002) 94(5):1593-1611.
66. SHULMAN T, SAUER FG, JACKMAN RM, CHANG CN, LANDOLFI NF: An antibody reactive with domain 4 of the platelet-derived growth factor beta receptor allows BB binding while inhibiting proliferation by impairing receptor dimerization. J. Biol. Chem. (1997) 272(28):17400-17404.
67. LOKKER NA, O'HARE JP, BARSOUMIAN A et al.: Functional importance of platelet-derived growth factor (PDGF) receptor extracellular immunoglobulin-like domains. Identification of PDGF binding site and neutralizing monoclonal antibodies. J. Biol. Chem. (1997) 272(52):33037-33044.
68. FERNS GA, RAINES EW, SPRUGEL KH, MOTANI AS, REIDY MA, ROSS R: Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science (1991) 253(5024):1129-1132.
69. SUN Q, JONES K, MCCLURE B et al.: Simultaneous antagonism of interleukin-5, granulocyte-macrophage colony-stimulating factor, and interleukin-3 stimulation of human eosinophils by targetting the common cytokine binding site of their receptors. Blood (1999) 94(6):1943-1951.
70. SHIMIZU N, SHIMIZU Y, MISKIMINS WK: EGF-ricin A conjugates: kinetic profiles of cytotoxic effects and resistant cell variants. Cell Struct. Funct. (1984) 9(3):203-212.
71. FEURING-BUSKE M, FRANKEL AE, ALEXANDER RL, GERHARD B, HOGGE DE: A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors. Cancer Res. (2002) 62(6):1730-1736.
72. FRANKEL AE, MCCUBREY JA, MILLER MS et al.: Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias. Leukemia (2000) 14(4):576-585.
73. SHAIKENOV TE, ADEKENOV SM, WILLIAMS RM et al.: Arglabin-DMA, a plant derived sesquiterpene, inhibits farnesyltransferase. Oncol. Rep. (2001) 8(1):173-179.
74. PRENDERGAST GC, RANE N: Farnesyltransferase inhibitors: mechanism and applications. Expert Opin. Investig. Drugs (2001) 10(12):2105-2116.
75. DU W, PRENDERGAST GC: Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res. (1999) 59(21):5492-5496.
76. WICKSTROM E: Oligonucleotide treatment of ras-induced tumors in nude mice. Mol. Biotechnol. (2001) 18(1):35-55.
77. MCPHILLIPS F, MULLEN P, MONIA BP et al.: Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer. Br. J. Cancer (2001) 85(11):1753-1758.
78. CHEN J, FUJII K, ZHANG L, ROBERTS T, FU H: Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc. Natl. Acad. Sci. USA (2001) 98(14):7783-7788.
79. LI K, ZHANG J: ISIS-3521. Isis Pharmaceuticals. Curr. Opin. Investig. Drugs (2001) 2(10):1454-1461.
80. BLAGOSKLONNY MV: Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia (2002) 16(4):455-462.
81. MARCU MG, CHADLI A, BOUHOUCHE I, CATELLI M, NECKERS LM: The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J. Biol. Chem. (2000) 275(47):37181-37186.
82. MULLINS DE, HAMUD F, REIM R, DAVIS HR: Inhibition of PDGF receptor binding and PDGF-stimulated biological activity in vitro and of intimal lesion formation in vivo by 2-bromomethyl-5-chlorobenzene sulfonylphthalimide. Arterioscler. Thromb. (1994) 14(7):1047-1055.
83. DUAN DS, PAZIN MJ, FRETTO LJ, WILLIAMS LT: A functional soluble extracellular region of the platelet-derived growth factor (PDGF) beta-receptor antagonizes PDGF-stimulated responses. J. Biol. Chem. (1991) 266(1):413-418.
84. TOULLEC D, PIANETTI P, COSTE H: The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J. Biol. Chem. (1991) 266(24):15771-15781.
85. LYONS JF, WILHELM S, HIBNER B, BOLLAG G: Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer (2001) 8(3):219-225.
86. HOTTE SJ, HIRTE HW: BAY 43-9006: early clinical data in patients with advanced solid malignancies. Curr. Pharm. Des. (2002) 8(25):2249-2253.
87. LACKEY K, CORY M, DAVIS R et al.: The discovery of potent cRaf1 kinase inhibitors. Bioorg. Med. Chem. Lett (2000) 10(3):223-226.
88. HEIMBROOK DC, HUBER HE, STIRDIVANT SM et al.: Identification of potent, selective kinase inhibitors of Raf. Annual Report of the Proceedings of the American Association of Cancer Research New Orleans, USA (1998). Abstract 3793.
89. DAVIES H, BIGNELL GR, COX C et al.: Mutations of the BRAF gene in human cancer. Nature (2002) 417(6892):949-954.
90. SEBOLT-LEOPOLD JS, DUDLEY DT, HERRERA R et al.: Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. (1999) 5(7):810-816.
91. ENGLISH JM, COBB MH: Pharmacological inhibitors of MAPK pathways. Trends Pharmacol. Sci. (2002) 23(1):40-45.
92. WILLIAMS DH, WILKINSON SE, PURTON T, LAMONT A, FLOTOW H, MURRAY EJ: Ro 09-2210 exhibits potent anti-proliferative effects on activated T cells by selectively blocking MKK activity. Biochemistry (1998) 37(26):9579-9585.
93. ZHAO A, LEE SH, MOJENA M, JENKINS RG et al.: Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK. J. Antibiot. (1999) 52(12):1086-1094.
94. ZHANG N, WU B, POWELL D et al.: Synthesis and structure-activity relationships of 3-cyano-4- (phenoxyanilino)quinolines as MEK (MAPKK) inhibitors. Bioorg. Med. Chem. Lett. (2000) 10(24):2825-2828.
95. TRAXLER P, BOLD G, BUCHDUNGER E et al.: Tyrosine kinase inhibitors: from rational design to clinical trials. Med. Res. Rev. (2001) 21(6):499-512.
96. LEVITZKI A, GAZIT A: Tyrosine kinase inhibition: an approach to drug development. Science (1995) 267(5205):1782-1788.
97. MAURO MJ, O'DWYER M, HEINRICH MC, DRUKER BJ: STI571: a paradigm of new agents for cancer therapeutics. J. Clin. Oncol. (2002) 20(1):325-334.
98. SUDBECK EA, LIU XP, NARLA RK et al.: Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin. Cancer Res. (1999) 5(6):1569-1582.
99. BURKE WM, JIN X, LIN HJ et al.: Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene (2001) 20(55):7925-7934.
100. THAVASU P, PROPPER D, MCDONALD A et al.: The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. Cancer Res. (1999) 59(16):3980-3984.
101. SATO S, FUJITA N, TSURUO T: Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene (2002) 21(11):1727-1738.
102. SCHULTZ H, ENGEL K, GAESTEL M: PMA-induced activation of the p42/44ERK- and p38RK-MAP kinase cascades in HL-60 cells is PKC dependent but not essential for differentiation to the macrophage-like phenotype. J. Cell. Physiol. (1997) 173(3):310-318.
103. TEICHER BA, ALVAREZ E, MENDELSOHN LG, ARA G, MENON K, WAYS DK: Enzymatic rationale and preclinical support for a potent protein kinase C beta inhibitor in cancer therapy. Adv. Enzyme Regul. (1999) 39:313-3127.
104. GOEKJIAN PG, JIROUSEK MR: Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Investig. Drug (2001) 10(12):2117-2140.
105. DAI Y, YU C, SINGH V et al.: Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. Cancer Res. (2001) 61(13):5106-5115.
106. YU C, KRYSTAL G, VARTICOVKSI L et al.: Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res. (2002) 62(1):188-199.
107. CARTER S, AUER KL, REARDON DB et al.: Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells. Oncogene (1998) 16(21):2787-2796.
108. CONTESSA JN, REARDON DB, TODD D et al.: The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells. Clin. Cancer Res. (1999) 5(2):405-411.
109. AMORINO GP, HAMILTON VM, VALERIE K, DENT P, LAMMERING G, SCHMIDT-ULLRICH RK: Epidermal growth factor receptor dependence of radiation-induced transcription factor activation in human breast carcinoma cells. Mol. Biol. Cell (2002) 13(7):2233-2244.
110. CARTEE L, SANKALA H, DAVIS C et al.: 7-Hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism. Int. J. Oncol. (2002) 21(2):351-359.
111. BLAGOSKLONNY MV: STI-571 must select for drug-resistant cells but 'no cell breathes fire out of its nostrils like a dragon'. Leukemia (2002) 16(4):570-572.
112. DRUKER BJ, SAWYERS CL, KANTARJIAN H et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. (2001) 344(14):1038-1042.
113. ZIMMERMANN S, MOELLING K: Phosphorylation and regulation of Raf by Akt (protein kinase B). Science (1999) 286(5445):1741-1744.