Inhibition of Ras for cancer treatment: The search continues

Future Medicinal Chemistry

Volumn 3, Issue 14, 2011, Pages 1787-1808

  Baines, Antonio T ^a   Xu, Dapeng ^a   Der, Channing J ^b  

^a NORTH CAROLINA CENTRAL UNIVERSITY   (United States)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; AZD 8330; CHIR 265; CYCLIN DEPENDENT KINASE INHIBITOR 2A; CYSMETHYNIL; DACARBAZINE; DOXORUBICIN; EVEROLIMUS; GGTI 2418; GSK1120212; GSK2118436; L 778123; LONAFARNIB; METHOTREXATE; MEVINOLIN; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; PACLITAXEL; PRAVASTATIN; RAS PROTEIN; SALIRASIB; SELUMETINIB; SMAD4 PROTEIN; SORAFENIB; TEMSIROLIMUS; TRANSFERASE INHIBITOR; UFT; UNCLASSIFIED DRUG; UNINDEXED DRUG; VEMURAFENIB; ZOLEDRONIC ACID;

ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; CANCER CELL CULTURE; CANCER CHEMOTHERAPY; CARCINOMA CELL; COLON CANCER; COLORECTAL CANCER; COLORECTAL CARCINOMA; DRUG BIOAVAILABILITY; DRUG MECHANISM; GENE SEQUENCE; GENETIC SCREENING; GLIOBLASTOMA; HUMAN; KIDNEY CARCINOMA; LETHALITY; LIVER CELL CARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; LUNG TUMOR; MELANOMA; MISSENSE MUTATION; NEUROBLASTOMA; NONHUMAN; ONCOGENE H RAS; ONCOGENE K RAS; ONCOGENE N RAS; OVARY CARCINOMA; PALMITOYLATION; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; RNA INTERFERENCE; SIGNAL TRANSDUCTION; SKIN CARCINOMA; SOLID TUMOR; THYROID PAPILLARY CARCINOMA;

ANTINEOPLASTIC AGENTS; GENES, RAS; GENOME-WIDE ASSOCIATION STUDY; HUMANS; MUTATION; NEOPLASMS; ONCOGENE PROTEIN P21(RAS); SIGNAL TRANSDUCTION;

EID: 80054936061     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.11.121     Document Type: Review

References (172)

1. Cox A, Der CJ. Ras history: the saga continues. Small GTPases 1, 1-27 (2010).
2. Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat. Rev. Mol. Cell. Biol. 9(7), 517-531 (2008). (Pubitemid 351881844)
3. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J. Clin. 60(5), 277-300 (2010).
4. Hruban RH, Wilentz RE, Kern SE. Genetic progression in the pancreatic ducts. Am. J. Pathol. 156(6), 1821-1825 (2000). (Pubitemid 30641750)
5. Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20(10), 1218-1249 (2006). (Pubitemid 43727584)
6. Yeh JJ, Der CJ. Targeting signal transduction in pancreatic cancer treatment. Exp. Opin. Ther. Targets 11(5), 673-694 (2007). (Pubitemid 46730082)
7. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53(4), 549-554 (1988).
8. Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897), 1801-1806 (2008).
9. Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327(6120), 298-303 (1987). (Pubitemid 17075080)
10. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 61 (5), 759-767 (1990).
11. Wood LD, Parsons DW, Jones S et al. The genomic landscapes of human breast and colorectal cancers. Science 318(5853), 1108-1113 (2007). (Pubitemid 350134889)
12. Ding L, Getz G, Wheeler DA et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216), 1069-1075 (2008).
13. Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319(9), 525-532 (1988).
14. Schaeffer BK, Glasner S, Kuhlmann E, Myles JL, Longnecker DS. Mutated c-K-ras in small pancreatic adenocarcinomas. Pancreas 9(2), 161-165 (1994). (Pubitemid 24063109)
15. Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260(5104), 85-88 (1993). (Pubitemid 23122749)
16. Chin L, Tam A, Pomerantz J et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400(6743), 468-472 (1999). (Pubitemid 29361802)
17. Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2(3), 243-247 (2002). (Pubitemid 41043979)
18. Lim KH, Baines AT, Fiordalisi JJ et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7(6), 533-545 (2005). (Pubitemid 40799247)
19. Herrmann C, Horn G, Spaargaren M, Wittinghofer A. Differential interaction of the ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor. J. Biol. Chem. 271(12), 6794-6800 (1996).
20. Fehrenbacher N, Bar-Sagi D, Philips M. Ras/ MAPK signaling from endomembranes. Mol. Oncol. 3(4), 297-307 (2009).
21. Sebti SM, Der CJ. Opinion: searching for the elusive targets of farnesyltransferase inhibitors. Nat. Rev. Cancer 3(12), 945-951 (2003). (Pubitemid 37500179)
22. Basso AD, Kirschmeier P, Bishop WR. Lipid posttranslational modifications. Farnesyl transferase inhibitors. J. Lipid Res. 47(1), 15-31 (2006).
23. Rowinsky EK. Lately, it occurs to me what a long, strange trip its been for the farnesyltransferase inhibitors. J. Clin. Oncol. 24(19), 2981-2984 (2006). (Pubitemid 46638928)
24. Willumsen BM, Christensen A, Hubbert NL, Papageorge AG, Lowy DR. The p21 ras C-terminus is required for transformation and membrane association. Nature 310(5978), 583-586 (1984). (Pubitemid 14053901)
25. Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57(7), 1167-1177 (1989). (Pubitemid 19169813)
26. Jackson JH, Cochrane CG, Bourne JR, Solski PA, Buss JE, Der CJ. Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation. Proc. Natl Acad. Sci. USA 87(8), 3042-3046 (1990).
27. Sinensky M, Beck LA, Leonard S, Evans R. Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis. J. Biol. Chem. 265(32), 19937-19941 (1990). (Pubitemid 120013953)
28. Reiss Y, Goldstein JL, Seabra MC, Casey PJ, Brown MS. Inhibition of purified p21ras farnesyl: protein transferase by Cys-AAX tetrapeptides. Cell 62(1), 81-88 (1990).
29. Reid TS, Long SB, Beese LS. Crystallographic analysis reveals that anticancer clinical candidate L-778,123 inhibits protein farnesyltransferase and geranylgeranyltransferase-I by different binding modes. Biochemistry 43(28), 9000-9008 (2004). (Pubitemid 38924434)
30. James GL, Goldstein JL, Brown MS et al. Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science 260(5116), 1937-1942 (1993). (Pubitemid 23258274)
31. Kohl NE, Mosser SD, deSolms SJ et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260(5116), 1934-1937 (1993). (Pubitemid 23258273)
32. Kohl NE, Omer CA, Conner MW et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat. Med. 1(8), 792-797 (1995).
33. Sepp-Lorenzino L, Ma Z, Rands E et al. A peptidomimetic inhibitor of farnesyl: protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res. 55(22), 5302-5309 (1995).
34. James G, Goldstein JL, Brown MS. Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells. Proc. Natl Acad. Sci. USA 93(9), 4454-4458 (1996).
35. Whyte DB, Kirschmeier P, Hockenberry TN et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272(22), 14459-14464 (1997). (Pubitemid 27232866)
36. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras In vivo. J. Biol. Chem. 272(22), 14093-14097 (1997). (Pubitemid 27232813)
37. Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15(11), 1283-1288 (1997). (Pubitemid 27429743)
38. Cox AD, Hisaka MM, Buss JE, Der CJ. Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras protein. Mol. Cell. Biol. 12(6), 2606-2615 (1992).
39. Hancock JF, Cadwallader K, Marshall CJ. Methylation and proteolysis are essential for efficient membrane binding of prenylated p21K-ras(B). EMBO J. 10(3), 641-646 (1991). (Pubitemid 21905518)
40. Cohen SJ, Ho L, Ranganathan S et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J. Clin. Oncol. 21(7), 1301-1306 (2003). (Pubitemid 46606407)
41. Van Cutsem E, van de Velde H, Karasek P et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 22(8), 1430-1438 (2004). (Pubitemid 41103625)
42. Macdonald JS, McCoy S, Whitehead RP et al. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a southwest oncology group (SWOG 9924) study. Invest. New Drugs 23(5), 485-487 (2005). (Pubitemid 41160096)
43. Basso AD, Mirza A, Liu G, Long BJ, Bishop WR, Kirschmeier P. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J. Biol. Chem. 280(35), 31101-31108 (2005). (Pubitemid 41291845)
44. Ellis CA, Vos MD, Howell H, Vallecorsa T, Fults DW, Clark GJ. Rig is a novel Ras-related protein and potential neural tumor suppressor. Proc. Natl Acad. Sci. USA 99(15), 9876-9881 (2002). (Pubitemid 34831140)
45. Luo RZ, Fang X, Marquez R et al. ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers. Oncogene 22(19), 2897-2909 (2003). (Pubitemid 36648916)
46. Elam C, Hesson L, Vos MD et al. RRP22 is a farnesylated, nucleolar, Ras-related protein with tumor suppressor potential. Cancer Res. 65(8), 3117-3125 (2005). (Pubitemid 40524592)
47. Yang SH, Bergo MO, Toth JI et al. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc. Natl Acad. Sci. USA 102(29), 10291-10296 (2005). (Pubitemid 41023365)
48. Mallampalli MP, Huyer G, Bendale P, Gelb MH, Michaelis S. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 102(40), 14416-14421 (2005). (Pubitemid 41429712)
49. Capell BC, Erdos MR, Madigan JP et al. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 102(36), 12879-12884 (2005). (Pubitemid 41282816)
50. Glynn MW, Glover TW. Incomplete processing of mutant lamin A in Hutchinson- Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum. Mol. Genet. 14(20), 2959-2969 (2005). (Pubitemid 41535461)
51. Fong LG, Frost D, Meta M et al. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science 311(5767), 1621-1623 (2006).
52. Davies BS, Fong LG, Yang SH, Coffinier C, Young SG. The posttranslational processing of prelamin A and disease. Ann. Rev. Genom. Hum. Genet. 10, 153-174 (2009).
53. Lerner EC, Qian Y, Blaskovich MA et al. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J. Biol. Chem. 270(45), 26802-26806 (1995). (Pubitemid 3007240)
54. Miquel K, Pradines A, Sun J et al. GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res. 57(10), 1846-1850 (1997). (Pubitemid 27209708)
55. Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/ G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J. Biol. Chem. 272(43), 27224-27229 (1997). (Pubitemid 27452683)
56. Liu M, Sjogren AK, Karlsson C et al. Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-Ras-induced lung cancer. Proc. Natl Acad. Sci. USA 107(14), 6471-6476 (2010).
57. Sjogren AK, Andersson KM, Khan O, Olofsson FJ, Karlsson C, Bergo MO. Inactivating GGTase-I reduces disease phenotypes in a mouse model of K-Ras-induced myeloproliferative disease. Leukemia 25(1), 186-189 (2011).
58. Lobell RB, Liu D, Buser CA et al. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl: protein transferase type-I. Mol. Cancer Ther. 1(9), 747-758 (2002).
59. Winter-Vann AM, Casey PJ. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat. Rev. Cancer 5(5), 405-412 (2005). (Pubitemid 40637832)
60. Kato K, Der CJ, Buss JE. Prenoids and palmitate: lipids that control the biological activity of Ras proteins. Semin. Cancer Biol. 3(4), 179-188 (1992).
61. Kim E, Ambroziak P, Otto JC et al. Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells. J. Biol. Chem. 274(13), 8383-8390 (1999). (Pubitemid 29164626)
62. Bergo MO, Leung GK, Ambroziak P, Otto JC, Casey PJ, Young SG. Targeted inactivation of the isoprenylcysteine carboxyl methyltransferase gene causes mislocalization of K-Ras in mammalian cells. J. Biol. Chem. 275(23), 17605-17610 (2000). (Pubitemid 30430806)
63. Wahlstrom AM, Cutts BA, Liu M et al. Inactivating Icmt ameliorates K-Ras-induced myeloproliferative disease. Blood 112(4), 1357-1365 (2008).
64. Wahlstrom AM, Cutts BA, Karlsson C et al. Rce1 deficiency accelerates the development of K-Ras-induced myeloproliferative disease. Blood 109(2), 763-768 (2007). (Pubitemid 46105979)
65. Manandhar SP, Hildebrandt ER, Schmidt WK. Small-molecule inhibitors of the Rce1p CaaX protease. J. Biomol. Screen 12(7), 983-993 (2007). (Pubitemid 47548599)
66. Porter SB, Hildebrandt ER, Breevoort SR, Mokry DZ, Dore TM, Schmidt WK. Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl (acyloxy)methyl ketones. Biochim. Biophys. Acta 1773(6), 853-862 (2007). (Pubitemid 46829435)
67. Wang M, Tan W, Zhou J et al. A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J. Biol. Chem. 283(27), 18678-18684 (2008).
68. Winter-Vann AM, Kamen BA, Bergo MO et al. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc. Natl Acad. Sci. USA 100(11), 6529-6534 (2003). (Pubitemid 36666615)
69. Buchanan MS, Carroll AR, Addepalli R, Avery VM, Hooper JN, Quinn RJ. Natural products, stylissadines A and B, specific antagonists of the P2X7 receptor, an important inflammatory target. J. Org. Chem. 72(7), 2309-2317 (2007). (Pubitemid 46536158)
70. Buchanan MS, Carroll AR, Fechner GA et al. Aplysamine 6, an alkaloidal inhibitor of Isoprenylcysteine carboxyl methyltransferase from the sponge Pseudoceratina sp. J. Nat. Prod. 71(6), 1066-1067 (2008). (Pubitemid 352008908)
71. Buchanan MS, Carroll AR, Fechner GA et al. Small-molecule inhibitors of the cancer target, isoprenylcysteine carboxyl methyltransferase, from Hovea parvicalyx. Phytochemistry 69(9), 1886-1889 (2008).
72. Ducker CE, Griffel LK, Smith RA et al. Discovery and characterization of inhibitors of human palmitoyl acyltransferases. Mol. Cancer Ther. 5(7), 1647-1659 (2006). (Pubitemid 44323232)
73. Draper JM, Smith CD. Palmitoyl acyltransferase assays and inhibitors (review). Mol. Membr. Biol. 26(1), 5-13 (2009).
74. Marshall CJ. Protein prenylation: a mediator of protein-protein interactions. Science 259(5103), 1865-1866 (1993). (Pubitemid 23124458)
75. Drugan JK, Khosravi-Far R, White MA et al. Ras interaction with two distinct binding domains in Raf-1 may be required for Ras transformation. J. Biol. Chem. 271(1), 233-237 (1996). (Pubitemid 26026583)
76. Niv H, Gutman O, Henis YI, Kloog Y. Membrane interactions of a constitutively active GFP-Ki-Ras 4B and their role in signaling. Evidence from lateral mobility studies. J. Biol. Chem. 274(3), 1606-1613 (1999).
77. Luo Z, Diaz B, Marshall MS, Avruch J. An intact Raf zinc finger is required for optimal binding to processed Ras and for ras-dependent Raf activation in situ. Mol. Cell. Biol. 17(1), 46-53 (1997). (Pubitemid 26425593)
78. Williams JG, Drugan JK, Yi GS, Clark GJ, Der CJ, Campbell SL. Elucidation of binding determinants and functional consequences of Ras/Raf-cysteine-rich domain interactions. J. Biol. Chem. 275(29), 22172-22179 (2000). (Pubitemid 30621798)
79. Marciano D, Ben-Baruch G, Marom M, Egozi Y, Haklai R, Kloog Y. Farnesyl derivatives of rigid carboxylic acids-inhibitors of ras-dependent cell growth. J. Med. Chem. 38(8), 1267-1272 (1995).
80. Marom M, Haklai R, Ben-Baruch G, Marciano D, Egozi Y, Kloog Y. Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylic acid. J. Biol. Chem. 270(38), 22263-22270 (1995).
81. Boufaied N, Wioland MA, Falardeau P, Gourdeau H. TLN-4601, a novel anticancer agent, inhibits Ras signaling post Ras prenylation and before MEK activation. Anticancer Drugs 21(5), 543-552 (2010).
82. Campbell PM, Boufaied N, Fiordalisi JJ et al. TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling. J. Mol. Signal 5, 18 (2010).
83. Blum R, Cox AD, Kloog Y. Inhibitors of chronically active ras: potential for treatment of human malignancies. Recent Pat. Anticancer Drug Discov. 3(1), 31-47 (2008). (Pubitemid 351223208)
84. Paz A, Haklai R, Elad-Sfadia G, Ballan E, Kloog Y. Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20(51), 7486-7493 (2001). (Pubitemid 33086908)
85. Elad-Sfadia G, Haklai R, Ballan E, Gabius HJ, Kloog Y. Galectin-1 augments Ras activation and diverts Ras signals to Raf-1 at the expense of phosphoinositide 3-kinase. J. Biol. Chem. 277(40), 37169-37175 (2002).
86. Haklai R, Weisz MG, Elad G et al. Dislodgment and accelerated degradation of Ras. Biochemistry 37(5), 1306-1314 (1998).
87. Jansen B, Schlagbauer-Wadl H, Kahr H et al. Novel Ras antagonist blocks human melanoma growth. Proc. Natl Acad. Sci. USA 96(24), 14019-14024 (1999).
88. Gana-Weisz M, Halaschek-Wiener J, Jansen B, Elad G, Haklai R, Kloog Y. The Ras inhibitor S-trans, trans-farnesylthiosalicylic acid chemosensitizes human tumor cells without causing resistance. Clin. Cancer Res. 8(2), 555-565 (2002). (Pubitemid 34193977)
89. Weisz B, Giehl K, Gana-Weisz M et al. A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice. Oncogene 18(16), 2579-2588 (1999). (Pubitemid 29216680)
90. Blum R, Jacob-Hirsch J, Amariglio N, Rechavi G, Kloog Y. Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1a, causing glycolysis shutdown and cell death. Cancer Res. 65(3), 999-1006 (2005). (Pubitemid 40216462)
91. Yaari S, Jacob-Hirsch J, Amariglio N, Haklai R, Rechavi G, Kloog Y. Disruption of cooperation between Ras and MycN in human neuroblastoma cells promotes growth arrest. Clin. Cancer Res. 11(12), 4321-4330 (2005). (Pubitemid 40825619)
92. Barkan B, Starinsky S, Friedman E, Stein R, Kloog Y. The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1. Clin. Cancer Res. 12(18), 5533-5542 (2006). (Pubitemid 44497271)
93. Goldberg L, Kloog Y. A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration. Cancer Res. 66(24), 11709-11717 (2006). (Pubitemid 46094183)
94. Shalom-Feuerstein R, Lindenboim L, Stein R, Cox AD, Kloog Y. Restoration of sensitivity to anoikis in Ras-transformed rat intestinal epithelial cells by a Ras inhibitor. Cell Death Differ. 11(2), 244-247 (2004). (Pubitemid 38159648)
95. Reif S, Weis B, Aeed H et al. The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats. J. Hepatol. 31(6), 1053-1061 (1999).
96. Haklai R, Elad-Sfadia G, Egozi Y, Kloog Y. Orally administered FTS (salirasib) inhibits human pancreatic tumor growth in nude mice. Cancer Chemother. Pharmacol. 61(1), 89-96 (2008). (Pubitemid 47512630)
97. McMahon LP, Yue W, Santen RJ, Lawrence Jr JC. Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex. Mol. Endocrinol. 19(1), 175-183 (2005). (Pubitemid 40065968)
98. Yue W, Wang J, Li Y, Fan P, Santen RJ. Farnesylthiosalicylic acid blocks mammalian target of rapamycin signaling in breast cancer cells. Int. J. Cancer 117(5), 746-754 (2005). (Pubitemid 41598825)
99. Hanker AB, Mitin N, Wilder RS et al. Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling. Oncogene 29(3), 380-391 (2009).
100. Bustinza-Linares E, Kurzrock R, Tsimberidou AM. Salirasib in the treatment of pancreatic cancer. Future Oncol. 6(6), 885-891 (2010).
101. Repasky GA, Chenette EJ, Der CJ. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell. Biol. 14(11), 639-647 (2004). (Pubitemid 39440613)
102. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26(22), 3291-3310 (2007). (Pubitemid 46763022)
103. Wong KK, Engelman JA, Cantley LC. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20(1), 87-90 (2010).
104. Vigil D, Martin TD, Williams F, Yeh JJ, Campbell SL, Der CJ. Aberrant overexpression of the Rgl2 Ral small GTPase-specific guanine nucleotide exchange factor promotes pancreatic cancer growth through Ral-dependent and Ral-independent mechanisms. J. Biol. Chem. 285(45), 34729-34740 (2010).
105. Malliri A, van Der Kammen RA, Clark K, van der Valk M, Michiels F, Collard JG. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417(6891), 867-871 (2002). (Pubitemid 34670335)
106. Bai Y, Edamatsu H, Maeda S et al. Crucial role of phospholipase Ce in chemical carcinogen-induced skin tumor development. Cancer Res. 64(24), 8808-8810 (2004). (Pubitemid 39665481)
107. Gonzalez-Garcia A, Pritchard CA, Paterson HF, Mavria G, Stamp G, Marshall CJ. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell. 7(3), 219-226 (2005). (Pubitemid 40568681)
108. Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24(1), 21-44 (2006). (Pubitemid 43108774)
109. Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr. Opin. Genet. Dev. 17(1), 31-39 (2007). (Pubitemid 46109299)
110. Smith RA, Dumas J, Adnane L, Wilhelm SM. Recent advances in the research and development of RAF kinase inhibitors. Curr. Top. Med. Chem. 6(11), 1071-1089 (2006). (Pubitemid 44110921)
111. Lyons JF, Wilhelm S, Hibner B, Bollag G. Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer 8(3), 219-225 (2001). (Pubitemid 32947644)
112. Wan PT, Garnett MJ, Roe SM et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116(6), 855-867 (2004). (Pubitemid 38410730)
113. 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. 64(19), 7099-7109 (2004). (Pubitemid 39331023)
114. Gattenlohner S, Etschmann B, Riedmiller H, Muller-Hermelink HK. Lack of KRAS and BRAF mutation in renal cell carcinoma. Eur. Urol. 55(6), 1490-1491 (2009).
115. Tannapfel A, Sommerer F, Benicke M et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52(5), 706-712 (2003). (Pubitemid 36528874)
116. Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol. Cancer Res. 6(5), 751-759 (2008).
117. Hatzivassiliou G, Song K, Yen I et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464(7287), 431-435 (2010).
118. Heidorn SJ, Milagre C, Whittaker S et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140(2), 209-221 (2010).
119. Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461(7263), 542-545 (2009).
120. Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363(9), 809-819 (2010).
121. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364(26), 2507-2516 (2011).
122. Bollag G, Hirth P, Tsai J et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467(7315), 596-599 (2010).
123. Johannessen CM, Boehm JS, Kim SY et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326), 968-972 (2010).
124. Nazarian R, Shi H, Wang Q et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-Ras upregulation. Nature 468(7326), 973-977 (2010).
125. Davies BR, Logie A, McKay JS et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action In vivo, pharmacokinetic/ pharmacodynamic relationship, and potential for combination in preclinical models. Mol. Cancer Ther. 6(8), 2209-2219 (2007). (Pubitemid 47294749)
126. Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ. Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/ or strong PI3K signalling in colorectal cancer cell lines. Int. J. Cancer 125(10), 2332-2341 (2009).
127. Martin TD, Samuel JC, Routh ED, Der CJ, Yeh JJ. Activation and involvement of Ral GTPases in colorectal cancer. Cancer Res. 71(1), 206-215 (2011).
128. Solit DB, Garraway LA, Pratilas CA et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439(7074), 358-362 (2006). (Pubitemid 43128863)
129. Pratilas CA, Taylor BS, Ye Q et al. (V600E) BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc. Natl Acad. Sci. USA 106(11), 4519-4524 (2009).
130. Adjei AA, Cohen RB, Franklin W et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J. Clin. Oncol. 26(13), 2139-2146 (2008).
131. Castellano E, Downward J. Role of RAS in the regulation of PI 3-kinase. Curr. Top. Microbiol. Immunol. 346, 143-169 (2011).
132. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/ Akt pathway in cancer. Oncogene 27(41), 5511-5526 (2008).
133. Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Exp. Opin. Investig. Drugs 17(11), 1717-1734 (2008).
134. Gupta S, Ramjaun AR, Haiko P et al. Binding of ras to phosphoinositide 3-kinase p110a is required for ras-driven tumorigenesis in mice. Cell 129(5), 957-968 (2007). (Pubitemid 46802703)
135. Engelman JA, Chen L, Tan X et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14(12), 1351-1356 (2008).
136. Yip-Schneider MT, Lin A, Barnard D, Sweeney CJ, Marshall MS. Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. Int. J. Oncol. 15(2), 271-279 (1999).
137. Rodriguez-Viciana P, McCormick F. RalGDS comes of age. Cancer Cell 7(3), 205-206 (2005). (Pubitemid 40568677)
138. Feig LA. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol. 13(8), 419-425 (2003). (Pubitemid 36897646)
139. Bodemann BO, White MA. Ral GTPases and cancer: linchpin support of the tumorigenic platform. Nat. Rev. Cancer 8(2), 133-140 (2008). (Pubitemid 351187648)
140. Urano T, Emkey R, Feig LA. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J. 15(4), 810-816 (1996). (Pubitemid 26064287)
141. Hamad NM, Elconin JH, Karnoub AE et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16(16), 2045-2057 (2002).
142. Lim KH, OHayer K, Adam SJ et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr. Biol. 16(24), 2385-2394 (2006). (Pubitemid 44894905)
143. Smith SC, Oxford G, Wu Z et al. The metastasis-associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer. Cancer Res. 66(4), 1917-1922 (2006).
144. Yin J, Pollock C, Tracy K et al. Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Mol. Cell. Biol. 27(21), 7538-7550 (2007). (Pubitemid 350033659)
145. Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat. Rev. Cancer 10(12), 842-857 (2010).
146. Falsetti SC, Wang DA, Peng H et al. Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Mol. Cell. Biol. 27(22), 8003-8014 (2007). (Pubitemid 350086432)
147. Wu JC, Chen TY, Yu CT et al. Identification of V23RalA-Ser194 as a critical mediator for Aurora-A-induced cellular motility and transformation by small pool expression screening. J. Biol. Chem. 280(10), 9013-9022 (2005).
148. Lim KH, Brady DC, Kashatus DF et al. Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Mol. Cell. Biol. 30(2), 508-523 (2010).
149. Molhoek KR, Brautigan DL, Slingluff CL Jr. Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin. J. Transl. Med. 3, 39 (2005).
150. Wang Z, Zhou J, Fan J et al. Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin. Cancer Res. 14(16), 5124-5130 (2008).
151. Legrier ME, Yang CP, Yan HG et al. Targeting protein translation in human non- small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. Cancer Res. 67(23), 11300-11308 (2007).
152. Flaherty KT. Chemotherapy and targeted therapy combinations in advanced melanoma. Clin. Cancer Res. 12(7 Pt 2), S2366-S2370 (2006).
153. McCubrey JA, Steelman LS, Chappell WH et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta 1773(8), 1263-1284 (2007). (Pubitemid 47125967)
154. Mabuchi S, Ohmichi M, Kimura A et al. Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J. Biol. Chem. 277(36), 33490-33500 (2002). (Pubitemid 34984873)
155. Abou-Alfa GK, Johnson P, Knox JJ et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 304(19), 2154-2160 (2010).
156. McDaid HM, Lopez-Barcons L, Grossman A et al. Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants. Cancer Res. 65(7), 2854-2860 (2005). (Pubitemid 40490089)
157. Rieber M, Rieber MS. Signaling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor UO126 in adherent or 3D spheroid melanoma irrespective of p53 status. Int. J. Cancer 118(5), 1135-1143 (2006). (Pubitemid 43185599)
158. Chung EJ, Brown AP, Asano H et al. In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/ extracellular signal-regulated kinase 1/2 kinase. Clin. Cancer Res. 15(9), 3050-3057 (2009).
159. Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan DE. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res. 62(16), 4671-4677 (2002).
160. Paglin S, Lee NY, Nakar C et al. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res. 65(23), 11061-11070 (2005). (Pubitemid 41713377)
161. Moretti L, Attia A, Kim KW, Lu B. Crosstalk between Bak/Bax and mTOR signaling regulates radiation-induced autophagy. Autophagy 3(2), 142-144 (2007). (Pubitemid 46449106)
162. Luo J, Emanuele MJ, Li D et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137(5), 835-848 (2009).
163. Scholl C, Frohling S, Dunn IF et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137(5), 821-834 (2009).
164. Barbie DA, Tamayo P, Boehm JS et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269), 108-112 (2009).
165. Kaelin WG Jr. Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med. 1(10), 99 (2009).
166. Chien Y, Kim S, Bumeister R et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127(1), 157-170 (2006). (Pubitemid 44472624)
167. Singh A, Greninger P, Rhodes D et al. A gene expression signature associated with K-Ras addiction reveals regulators of EMT and tumor cell survival. Cancer Cell 15(6), 489-500 (2009).
168. Babij C, Zhang Y, Kurzeja RJ et al. STK33 kinase activity is non-essential in KRAS-dependent cancer cells. Cancer Res. 71(17), 5818-5826 (2011).
169. Wellcome Trust Sanger Institute. www.sanger.ac.uk/genetics/CGP/cosmic/
170. Progeria Research Foundation. www.progeriaresearch.org/
171. Tigris Pharmaceuticals. www.tigrispharma.com
172. Clinicaltrials. http://clinicaltrials.gov