Papers of special note have been highlighted as either of interest (λ) or of special interest (λλ) to readers.
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Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol. 2006;16(24):2385–2394. [PubMed] 13. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441(7092):424–430. [PubMed] 14. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26(22):3291–3310. [PubMed] 15. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62(23):6997–7000. [PubMed] 16. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–954. [PubMed]λλ First work demonstrating activating mutations in B-Raf in human cancers 17. Forbes S, Clements J, Dawson E, et al. Cosmic 2005. Br J Cancer. 2006;94(2):318–322. [PMC free article] [PubMed] 18. Zebisch A, Staber PB, Delavar A, et al. Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia. Cancer Res. 2006;66(7):3401–3408. [PubMed] 19. Heidecker G, Huleihel M, Cleveland JL, et al. Mutational activation of c-raf-1 and definition of the minimal transforming sequence. Mol Cell Biol. 1990;10(6):2503–2512. [PMC free article] [PubMed] 20. Fransen K, Klintenas M, Osterstrom A, et al. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis. 2004;25(4):527–533. [PubMed] 21. Emuss V, Garnett M, Mason C, Marais R. Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res. 2005;65(21):9719–9726. [PubMed] 22. Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem. 2005;280(16):16244–16253. [PubMed] 23. Giroux S, Tremblay M, Bernard D, et al. Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol. 1999;9(7):369–372. [PubMed] 24. Hood JD, Bednarski M, Frausto R, et al. Tumor regression by targeted gene delivery to the neovasculature. Science. 2002;296(5577):2404–2407. [PubMed] 25. Murphy DA, Makonnen S, Lassoued W, et al. Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006) Am J Pathol. 2006;169(5):1875–1885. [PubMed] 26. Zhu WH, Macintyre A, Nicosia RF. Regulation of angiogenesis by vascular endothelial growth factor and angiopoietin-1 in the rat aorta model: distinct temporal patterns of intracellular signaling correlate with induction of angiogenic sprouting. Am J Pathol. 2002;161(3):823–830. [PubMed] 27. Ilan N, Mahooti S, Madri JA. Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis. 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Biochem J. 2000;351 Pt 2:289–305. [PubMed] 33. Mcphillips F, Mullen P, Macleod KG, et al. Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis. 2006;27(4):729–739. [PubMed] 34. Galabova-Kovacs G, Kolbus A, Matzen D, et al. ERK and beyond: insights from B-Raf and Raf-1 conditional knockouts. Cell Cycle. 2006;5(14):1514–1518. [PubMed] 35. 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 U S A. 2001;98(14):7783–7788. [PubMed]
36. Galmiche A, Fueller J. RAF kinases and mitochondria. Biochim Biophys Acta. 2006
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Cell. 1996;87(4):629–638. [PubMed] 43. Caraglia M, Marra M, Viscomi C, et al. The farnesyltransferase inhibitor R115777 (ZARNESTRA(R)) enhances the pro-apoptotic activity of interferon-alpha through the inhibition of multiple survival pathways. Int J Cancer. 2007 [PubMed] 44. Alavi AS, Acevedo L, Min W, Cheresh DA. Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res. 2007;67(6):2766–2772. [PubMed] 45. O'neill E, Rushworth L, Baccarini M, Kolch W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science. 2004;306(5705):2267–2270. [PubMed] 46. Lamberti A, Longo O, Marra M, et al. C-Raf antagonizes apoptosis induced by IFN-alpha in human lung cancer cells by phosphorylation and increase of the intracellular content of elongation factor 1A. Cell Death Differ. 2007;14(5):952–962. [PubMed] 47. Janosch P, Kieser A, Eulitz M, et al. The Raf-1 kinase associates with vimentin kinases and regulates the structure of vimentin filaments. Faseb J. 2000;14(13):2008–2021. [PubMed] 48. Ehrenreiter K, Piazzolla D, Velamoor V, et al. Raf-1 regulates Rho signaling and cell migration. J Cell Biol. 2005;168(6):955–964. [PMC free article] [PubMed] 49. Ku NO, Fu H, Omary MB. Raf-1 activation disrupts its binding to keratins during cell stress. J Cell Biol. 2004;166(4):479–485. [PMC free article] [PubMed] 50. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–867. [PubMed]λλ Structural analysis of wild type and mutant B-Raf kinase domain. Co-complex with sorafenib reveals mechanism of inhibitor action. 51. Terada T, Ito Y, Shirouzu M, et al. Nuclear magnetic resonance and molecular dynamics studies on the interactions of the Ras-binding domain of Raf-1 with wild-type and mutant Ras proteins. J Mol Biol. 1999;286(1):219–232. [PubMed] 52. Mott HR, Carpenter JW, Zhong S, et al. The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site. Proc Natl Acad Sci U S A. 1996;93(16):8312–8317. [PubMed] 53. Williams JG, Drugan JK, Yi GS, et al. Elucidation of binding determinants and functional consequences of Ras/Raf-cysteine-rich domain interactions. J Biol Chem. 2000;275(29):22172–22179. [PubMed] 54. Monia BP, Sasmor H, Johnston JF, et al. Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C-raf kinase supports an antisense mechanism of action in vivo. Proc Natl Acad Sci U S A. 1996;93(26):15481–15484. [PubMed] 55. Monia BP, Johnston JF, Geiger T, Muller M, Fabbro D. Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nat Med. 1996;2(6):668–675. [PubMed] 56. Britten RA, Perdue S, Eshpeter A, Merriam D. Raf-1 kinase activity predicts for paclitaxel resistance in TP53mut, but not TP53wt human ovarian cancer cells. Oncol Rep. 2000;7(4):821–825. [PubMed] 57. Mullen P, Mcphillips F, Monia BP, Smyth JF, Langdon SP. Comparison of strategies targeting Raf-1 mRNA in ovarian cancer. Int J Cancer. 2006;118(6):1565–1571. [PubMed] 58. Geiger T, Muller M, Monia BP, Fabbro D. Antitumor activity of a C-raf antisense oligonucleotide in combination with standard chemotherapeutic agents against various human tumors transplanted subcutaneously into nude mice. Clin Cancer Res. 1997;3(7):1179–1185. [PubMed] 59. Islam A, Handley SL, Thompson KS, Akhtar S. Studies on uptake, sub-cellular trafficking and efflux of antisense oligodeoxynucleotides in glioma cells using self-assembling cationic lipoplexes as delivery systems. J Drug Target. 2000;7(5):373–382. [PubMed] 60. Gokhale PC, Mcrae D, Monia BP, et al. Antisense raf oligodeoxyribonucleotide is a radiosensitizer in vivo. Antisense Nucleic Acid Drug Dev. 1999;9(2):191–201. [PubMed] 61. Rudin CM, Holmlund J, Fleming GF, et al. Phase I Trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer. Clin Cancer Res. 2001;7(5):1214–1220. [PubMed] 62. Cunningham CC, Holmlund JT, Schiller JH, et al. A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res. 2000;6(5):1626–1631. [PubMed] 63. O'dwyer PJ, Stevenson JP, Gallagher M, et al. c-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A) Clin Cancer Res. 1999;5(12):3977–3982. [PubMed] 64. Stevenson JP, Yao KS, Gallagher M, et al. Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A) J Clin Oncol. 1999;17(7):2227–2236. [PubMed] 65. Tolcher AW, Reyno L, Venner PM, et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2002;8(8):2530–2535. [PubMed] 66. Oza AM, Elit L, Swenerton K, et al. Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116) Gynecol Oncol. 2003;89(1):129–133. [PubMed] 67. Cripps MC, Figueredo AT, Oza AM, et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study. Clin Cancer Res. 2002;8(7):2188–2192. [PubMed] 68. Gokhale PC, Zhang C, Newsome JT, et al. Pharmacokinetics, toxicity, and efficacy of ends-modified raf antisense oligodeoxyribonucleotide encapsulated in a novel cationic liposome. Clin Cancer Res. 2002;8(11):3611–3621. [PubMed] 69. Pei J, Zhang C, Gokhale PC, et al. Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine. Anticancer Drugs. 2004;15(3):243–253. [PubMed] 70. Mewani RR, Tang W, Rahman A, et al. Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models. Int J Oncol. 2004;24(5):1181–1188. [PubMed] 71. Rudin CM, Marshall JL, Huang CH, et al. Delivery of a liposomal c-raf-1 antisense oligonucleotide by weekly bolus dosing in patients with advanced solid tumors: a phase I study. Clin Cancer Res. 2004;10(21):7244–7251. [PubMed] 72. Dritschilo A, Huang CH, Rudin CM, et al. Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies. 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Systemic delivery of RafsiRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer. Int J Oncol. 2005;26(4):1087–1091. [PubMed] 78. Leng Q, Mixson AJ. Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo. Cancer Gene Ther. 2005;12(8):682–690. [PubMed] 79. Fabian MA, Biggs WH, 3RD, Treiber DK, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005;23(3):329–336. [PubMed]λλ Extremely comprehensive analysis of the specificity profiles of small molecule kinase inhibitors, based on direct in vitro substrate binding assays. Identification of inhibitors active against kinases with resistance mutations provides the basis for follow-up clinical investigations. 80. Lyons JF, Wilhelm S, Hibner B, Bollag G. Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer. 2001;8(3):219–225. [PubMed] 81. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–7109. [PubMed]λ Extensive pre-clinical characterization of sorafenib. 82. Lee JT, Mccubrey JA. BAY-43-9006 Bayer/Onyx. Curr Opin Investig Drugs. 2003;4(6):757–763. [PubMed] 83. 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. [PubMed] 84. Carlomagno F, Anaganti S, Guida T, et al. BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006;98(5):326–334. [PubMed] 85. Chang YS, Adnane J, Trail PA, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59(5):561–574. [PubMed] 86. Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene. 2005;24(46):6861–6869. [PubMed] 87. Panka DJ, Wang W, Atkins MB, Mier JW The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Cancer Res. 2006;66(3):1611–1619. [PubMed]λ Describes the mechanistic basis for AIF-dependent, MEK-independent, sorafenib-induced apoptosis 88. Rahmani M, Davis EM, Bauer C, Dent P, Grant S. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005;280(42):35217–35227. [PubMed] 89. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–11858. [PubMed] 90. Strumberg D, Clark JW, Awada A, et al. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist. 2007;12(4):426–437. [PubMed] 91. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006;24(9):1363–1369. [PubMed] 92. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–134. [PubMed]λλ Data from pivotal phase III trial indicating significant improvement in progression-free survival for sorafenib-treated patients with advanced refractory RCC. Basis for FDA approval of sorafenib for this cancer. 93. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24(26):4293–4300. [PubMed]
94. Llovet J, Ricci S, Mazzaferro V, et al. Am. Soc. Clin. Oncol. Chicago: 2007. Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC: Results of a Phase III randomized placebo-controlled trial (SHARP trial)λ Study demonstrates increased overall survival of HCC patients treated with sorafenib versus placebo.
95. Fecher LA, Cummings SD, Keefe MJ, Alani RM Toward a molecular classification of melanoma. J Clin Oncol. 2007;25(12):1606–1620. [PubMed]λ Study defines the heterogenous molecular subtypes of melanoma, providing criteria which may have clinical validity for design of targeted therapies involving Raf pathway-targeted drugs. 96. Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95(5):581–586. [PMC free article] [PubMed]
97. Adnane L, Trail PA, Wilhelm S. Am. Assoc. Cancer Res. Natl. Cancer Inst. Philadelphia, PA: 2005. Sorafenib (BAY 43-9006) antagonizes Raf function not only by inhibiting Raf kinase activity but also by sequestering Raf protein into non-functional complexes.
98. Ryan CW, Goldman BH, Lara PN, Jr, et al. Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group. J Clin Oncol. 2007;25(22):3296–3301. [PubMed] 99. Gollob JA, Rathmell WK, Richmond TM, et al. Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol. 2007;25(22):3288–3295. [PubMed]
100. Sala E, Mologni L, Gamacorti-Passerini C. New selective B-RAF inhibitor leads to re-differentiation and growth arrest through up-regulation of p21CIP/WAF in anaplastic thyroid carcinoma cell lines; AACR 98th Meeting; Los Angeles; 2007.
101. Hall-Jackson CA, Eyers PA, Cohen P, et al. Paradoxical activation of Raf by a novel Raf inhibitor. Chem Biol. 1999;6(8):559–568. [PubMed] 102. Van Gompel JJ, Kunnimalaiyaan M, Holen K, Chen H. ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells. Mol Cancer Ther. 2005;4(6):910–97. [PubMed] 103. Kappes A, Vaccaro A, Kunnimalaiyaan M, Chen H. ZM336372, a Raf-1 activator, inhibits growth of pheochromocytoma cells. J Surg Res. 2006;133(1):42–45. [PubMed] 104. Houben R, Ortmann S, Schrama D, et al. Activation of the MAP Kinase Pathway Induces Apoptosis in the Merkel Cell Carcinoma Cell Line UISO. J Invest Dermatol. 2007 [PubMed]
105. Shen M, Wu A, Aquila B, Lyne P, Drew L. Linking molecular characteristics to the pharmacological response of a panel of cancer cell lines to the BRAF inhibitor, AZ628; AACR 98th Meeting; Los Angeles; 2007.
106. Tsai J, Zhang J, Bremer R, et al. Development of a novel inhibitor of oncogenic B-Raf; AACR 97th Meeting; Washington, D.C: 2006.
107. Amiri P, Aikawa ME, Dove J, et al. CHIR-265 is a potent selective inhibitor of c-Raf/B-Raf/mutB-Raf that effectively inhibits proliferation and survival of cancer cell lines with Ras/Raf pathway mutations; AACR 97th Meeting; Washington D.C: 2006.
108. Sathornsumetee S, Hjelmeland AB, Keir ST, et al. AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma. Cancer Res. 2006;66(17):8722–8730. [PubMed] 109. Mitsiades CS, Negri J, Mcmullan C, et al. Targeting BRAFV600E in thyroid carcinoma: therapeutic implications. Mol Cancer Ther. 2007;6(3):1070–1078. [PubMed] 110. Ouyang B, Knauf JA, Smith EP, et al. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res. 2006;12(6):1785–1793. [PubMed] 111. Lu Y, Sakamuri S, Chen QZ, et al. Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator. Bioorganic & Medicinal Chemistry Letters. 2004;14(15):3957–3962. [PubMed] 112. Kato-Stankiewicz J, Hakimi I, Zhi G, et al. 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[PubMed]λλ Defined differential roles for Hsp90 in wild type versus mutated Raf proteins, and provided a scientific rationale for combination of HSP90 inhibitors with Raf-kinase directed inhibitors. 117. Workman P, Burrows F, Neckers L, Rosen N. Drugging the cancer chaperone HSP90: Combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci. 2007 [PubMed] 118. Miyata Y. Hsp90 inhibitor geldanamycin and its derivatives as novel cancer chemotherapeutic agents. Curr Pharm Des. 2005;11(9):1131–1138. [PubMed] 119. Heath EI, Gaskins M, Pitot HC, et al. A phase II trial of 17-allylamino-17- demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin Prostate Cancer. 2005;4(2):138–141. [PubMed] 120. Ronnen EA, Kondagunta GV, Ishill N, et al. A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma. Invest New Drugs. 2006;24(6):543–546. [PubMed] 121. 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