Inhibition of Ras for cancer treatment: the search continues

Papers of special note have been highlighted as: ▪ of interest

Bibliography

• 1  Cox A, Der CJ. Ras history: the saga continues. Small GTPases1,1–27 (2010).
  MedlineGoogle Scholar
• 2  Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat. Rev. Mol. Cell. Biol.9(7),517–531 (2008).
  Medline CASGoogle Scholar
• 3  Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J. Clin.60(5),277–300 (2010).
  MedlineGoogle Scholar
• 4  Hruban RH, Wilentz RE, Kern SE. Genetic progression in the pancreatic ducts. Am. J. Pathol.156(6),1821–1825 (2000).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 6  Yeh JJ, Der CJ. Targeting signal transduction in pancreatic cancer treatment. Exp. Opin. Ther. Targets11(5),673–694 (2007).
  Medline CASGoogle Scholar
• 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. Cell53(4),549–554 (1988).
  Medline CASGoogle Scholar
• 8  Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science321(5897),1801–1806 (2008).▪ K-Ras signaling was found to be genetically altered in 100% of pancreatic tumors analyzed, confirming the importance of K-Ras as a potential therapeutic target in pancreatic cancer.
  Medline CASGoogle Scholar
• 9  Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature327(6120),298–303 (1987).
  Medline CASGoogle Scholar
• 10  Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell61(5),759–767 (1990).
  Medline CASGoogle Scholar
• 11  Wood LD, Parsons DW, Jones S et al. The genomic landscapes of human breast and colorectal cancers. Science318(5853),1108–1113 (2007).
  Medline CASGoogle Scholar
• 12  Ding L, Getz G, Wheeler DA et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature455(7216),1069–1075 (2008).
  Medline CASGoogle Scholar
• 13  Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med.319(9),525–532 (1988).
  Medline CASGoogle Scholar
• 14  Schaeffer BK, Glasner S, Kuhlmann E, Myles JL, Longnecker DS. Mutated c-K-ras in small pancreatic adenocarcinomas. Pancreas9(2),161–165 (1994).
  Medline CASGoogle Scholar
• 15  Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science260(5104),85–88 (1993).
  Medline CASGoogle Scholar
• 16  Chin L, Tam A, Pomerantz J et al. Essential role for oncogenic Ras in tumour maintenance. Nature400(6743),468–472 (1999).
  Medline CASGoogle Scholar
• 17  Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell2(3),243–247 (2002).
  Medline CASGoogle Scholar
• 18  Lim KH, Baines AT, Fiordalisi JJ et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell7(6),533–545 (2005).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 20  Fehrenbacher N, Bar-Sagi D, Philips M. Ras/MAPK signaling from endomembranes. Mol. Oncol.3(4),297–307 (2009).
  Medline CASGoogle Scholar
• 21  Sebti SM, Der CJ. Opinion: searching for the elusive targets of farnesyltransferase inhibitors. Nat. Rev. Cancer3(12),945–951 (2003).
  Medline CASGoogle Scholar
• 22  Basso AD, Kirschmeier P, Bishop WR. Lipid posttranslational modifications. Farnesyl transferase inhibitors. J. Lipid Res.47(1),15–31 (2006).
  Medline CASGoogle Scholar
• 23  Rowinsky EK. Lately, it occurs to me what a long, strange trip it’s been for the farnesyltransferase inhibitors. J. Clin. Oncol.24(19),2981–2984 (2006).
  Medline CASGoogle Scholar
• 24  Willumsen BM, Christensen A, Hubbert NL, Papageorge AG, Lowy DR. The p21 ras C-terminus is required for transformation and membrane association. Nature310(5978),583–586 (1984).
  Medline CASGoogle Scholar
• 25  Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell57(7),1167–1177 (1989).
  Medline CASGoogle Scholar
• 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. USA87(8),3042–3046 (1990).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 28  Reiss Y, Goldstein JL, Seabra MC, Casey PJ, Brown MS. Inhibition of purified p21ras farnesyl: protein transferase by Cys-AAX tetrapeptides. Cell62(1),81–88 (1990).
  Medline CASGoogle Scholar
• 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. Biochemistry43(28),9000–9008 (2004).
  Medline CASGoogle Scholar
• 30  James GL, Goldstein JL, Brown MS et al. Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science260(5116),1937–1942 (1993).
  Medline CASGoogle Scholar
• 31  Kohl NE, Mosser SD, deSolms SJ et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science260(5116),1934–1937 (1993).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 34  James G, Goldstein JL, Brown MS. Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells. Proc. Natl Acad. Sci. USA93(9),4454–4458 (1996).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).▪ Provided evidence why farnesyltransferase inhibitors were not effective against cancers dependent on K-ras signaling.
  Medline CASGoogle Scholar
• 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. Oncogene15(11),1283–1288 (1997).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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 Drugs23(5),485–487 (2005).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. USA99(15),9876–9881 (2002).
  Medline CASGoogle Scholar
• 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. Oncogene22(19),2897–2909 (2003).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. USA102(29),10291–10296 (2005).
  Medline CASGoogle Scholar
• 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. USA102(40),14416–14421 (2005).
  Medline CASGoogle Scholar
• 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. USA102(36),12879–12884 (2005).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 51  Fong LG, Frost D, Meta M et al. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science311(5767),1621–1623 (2006).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. USA107(14),6471–6476 (2010).
  Medline CASGoogle Scholar
• 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. Leukemia25(1),186–189 (2011).
  MedlineGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 59  Winter-Vann AM, Casey PJ. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat. Rev. Cancer5(5),405–412 (2005).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 63  Wahlstrom AM, Cutts BA, Liu M et al. Inactivating Icmt ameliorates K-Ras-induced myeloproliferative disease. Blood112(4),1357–1365 (2008).
  Medline CASGoogle Scholar
• 64  Wahlstrom AM, Cutts BA, Karlsson C et al. Rce1 deficiency accelerates the development of K-Ras-induced myeloproliferative disease. Blood109(2),763–768 (2007).
  Medline CASGoogle Scholar
• 65  Manandhar SP, Hildebrandt ER, Schmidt WK. Small-molecule inhibitors of the Rce1p CaaX protease. J. Biomol. Screen12(7),983–993 (2007).
  Medline CASGoogle Scholar
• 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. Acta1773(6),853–862 (2007).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. USA100(11),6529–6534 (2003).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 71  Buchanan MS, Carroll AR, Fechner GA et al. Small-molecule inhibitors of the cancer target, isoprenylcysteine carboxyl methyltransferase, from Hovea parvicalyx. Phytochemistry69(9),1886–1889 (2008).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 73  Draper JM, Smith CD. Palmitoyl acyltransferase assays and inhibitors (review). Mol. Membr. Biol.26(1),5–13 (2009).
  Medline CASGoogle Scholar
• 74  Marshall CJ. Protein prenylation: a mediator of protein–protein interactions. Science259(5103),1865–1866 (1993).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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 Drugs21(5),543–552 (2010).
  Medline CASGoogle Scholar
• 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. Signal5,18 (2010).
  MedlineGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. Oncogene20(51),7486–7493 (2001).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 86  Haklai R, Weisz MG, Elad G et al. Dislodgment and accelerated degradation of Ras. Biochemistry37(5),1306–1314 (1998).
  Medline CASGoogle Scholar
• 87  Jansen B, Schlagbauer-Wadl H, Kahr H et al. Novel Ras antagonist blocks human melanoma growth. Proc. Natl Acad. Sci. USA96(24),14019–14024 (1999).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 89  Weisz B, Giehl K, Gana-Weisz M et al. A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice. Oncogene18(16),2579–2588 (1999).
  Medline CASGoogle Scholar
• 90  Blum R, Jacob-Hirsch J, Amariglio N, Rechavi G, Kloog Y. Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1α, causing glycolysis shutdown and cell death. Cancer Res.65(3),999–1006 (2005).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. Cancer117(5),746–754 (2005).
  Medline CASGoogle Scholar
• 99  Hanker AB, Mitin N, Wilder RS et al. Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling. Oncogene29(3),380–391 (2009).
  MedlineGoogle Scholar
• 100  Bustinza-Linares E, Kurzrock R, Tsimberidou AM. Salirasib in the treatment of pancreatic cancer. Future Oncol.6(6),885–891 (2010).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 102  Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene26(22),3291–3310 (2007).
  Medline CASGoogle Scholar
• 103  Wong KK, Engelman JA, Cantley LC. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev.20(1),87–90 (2010).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. Nature417(6891),867–871 (2002).
  Medline CASGoogle Scholar
• 106  Bai Y, Edamatsu H, Maeda S et al. Crucial role of phospholipase Cε in chemical carcinogen-induced skin tumor development. Cancer Res.64(24),8808–8810 (2004).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 108  Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors24(1),21–44 (2006).
  Medline CASGoogle Scholar
• 109  Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr. Opin. Genet. Dev.17(1),31–39 (2007).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 111  Lyons JF, Wilhelm S, Hibner B, Bollag G. Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer8(3),219–225 (2001).
  Medline CASGoogle Scholar
• 112  Wan PT, Garnett MJ, Roe SM et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell116(6),855–867 (2004).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 115  Tannapfel A, Sommerer F, Benicke M et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut52(5),706–712 (2003).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 117  Hatzivassiliou G, Song K, Yen I et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature464(7287),431–435 (2010).
  Medline CASGoogle Scholar
• 118  Heidorn SJ, Milagre C, Whittaker S et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell140(2),209–221 (2010).
  Medline CASGoogle Scholar
• 119  Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature461(7263),542–545 (2009).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 122  Bollag G, Hirth P, Tsai J et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature467(7315),596–599 (2010).
  Medline CASGoogle Scholar
• 123  Johannessen CM, Boehm JS, Kim SY et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature468(7326),968–972 (2010).
  Medline CASGoogle Scholar
• 124  Nazarian R, Shi H, Wang Q et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-Ras upregulation. Nature468(7326),973–977 (2010).▪ Diversity in mechanisms of resistance in melanomas treated with a BRAF inhibitor.
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. Cancer125(10),2332–2341 (2009).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 128  Solit DB, Garraway LA, Pratilas CA et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature439(7074),358–362 (2006).▪ Cell dependency of MEK signaling is influenced by mutations in BRAF and KRas.
  Medline CASGoogle Scholar
• 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. USA106(11),4519–4524 (2009).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 131  Castellano E, Downward J. Role of RAS in the regulation of PI 3-kinase. Curr. Top. Microbiol. Immunol.346,143–169 (2011).
  Google Scholar
• 132  Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene27(41),5511–5526 (2008).
  Medline CASGoogle Scholar
• 133  Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Exp. Opin. Investig. Drugs17(11),1717–1734 (2008).
  Medline CASGoogle Scholar
• 134  Gupta S, Ramjaun AR, Haiko P et al. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell129(5),957–968 (2007).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 137  Rodriguez-Viciana P, McCormick F. RalGDS comes of age. Cancer Cell7(3),205–206 (2005).
  Medline CASGoogle Scholar
• 138  Feig LA. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol.13(8),419–425 (2003).
  Medline CASGoogle Scholar
• 139  Bodemann BO, White MA. Ral GTPases and cancer: linchpin support of the tumorigenic platform. Nat. Rev. Cancer8(2),133–140 (2008).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 142  Lim KH, O’Hayer 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 145  Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat. Rev. Cancer10(12),842–857 (2010).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  MedlineGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 152  Flaherty KT. Chemotherapy and targeted therapy combinations in advanced melanoma. Clin. Cancer Res.12(7 Pt 2),S2366–S2370 (2006).
  Google Scholar
• 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. Acta1773(8),1263–1284 (2007).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. JAMA304(19),2154–2160 (2010).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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. Cancer118(5),1135–1143 (2006).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 161  Moretti L, Attia A, Kim KW, Lu B. Crosstalk between Bak/Bax and mTOR signaling regulates radiation-induced autophagy. Autophagy3(2),142–144 (2007).
  Medline CASGoogle Scholar
• 162  Luo J, Emanuele MJ, Li D et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell137(5),835–848 (2009).
  Medline CASGoogle Scholar
• 163  Scholl C, Frohling S, Dunn IF et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell137(5),821–834 (2009).
  Medline CASGoogle Scholar
• 164  Barbie DA, Tamayo P, Boehm JS et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature462(7269),108–112 (2009).
  Medline CASGoogle Scholar
• 165  Kaelin WG Jr. Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med.1(10),99 (2009).
  MedlineGoogle Scholar
• 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. Cell127(1),157–170 (2006).
  Medline CASGoogle Scholar
• 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 Cell15(6),489–500 (2009).
  Medline CASGoogle Scholar
• 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).
  Medline CASGoogle Scholar
• 201  Wellcome Trust Sanger Institute. www.sanger.ac.uk/genetics/CGP/cosmic/
  Google Scholar
• 202  Progeria Research Foundation. www.progeriaresearch.org/
  Google Scholar
• 203  Tigris Pharmaceuticals. www.tigrispharma.com
  Google Scholar
• 204  Clinicaltrials. http://clinicaltrials.gov
  Google Scholar