Skip to main content
SpringerLink
Log in
Book cover

Ras Superfamily Small G Proteins: Biology and Mechanisms 1 pp 135–156Cite as

Targeting the Raf-MEK-ERK Mitogen-Activated Protein Kinase Cascade for the Treatment of RAS Mutant Cancers

  • Chapter
  • First Online:

Abstract

The three RAS genes comprise the most frequently mutated oncogene family in human cancer; furthermore, substantial experimental evidence supports their key driver roles in cancer development and growth. Consequently, there has been considerable interest and effort in developing therapeutic approaches for blocking aberrant Ras function for cancer treatment. Despite over three decades of intensive effort, to date no effective anti-Ras therapeutic approaches have reached the clinic. Currently, the most promising direction involves inhibitors of Ras effector signaling, with the Raf-MEK-ERK mitogen-activated protein kinase cascade the most intensively pursued. Presently, there are at least 33 inhibitors of this pathway under clinical evaluation. In this chapter, we provide a summary of this key Ras effector signaling network and the efforts to target the Raf-MEK-ERK cascade for the treatment of RAS mutant cancers.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Bai Y, Edamatsu H, Maeda S, Saito H, Suzuki N, Satoh T, Kataoka T (2004) Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res 64:8808–8810

    Article  PubMed  CAS  Google Scholar 

  • Blasco RB, Francoz S, Santamaria D, Canamero M, Dubus P, Charron J, Baccarini M, Barbacid M (2011) c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. Cancer Cell 19:652–663

    Article  PubMed  CAS  Google Scholar 

  • Brummelkamp TR, Bernards R, Agami R (2002) Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2:243–247

    Article  PubMed  CAS  Google Scholar 

  • Campbell PM, Groehler AL, Lee KM, Ouellette MM, Khazak V, Der CJ (2007) K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res 67:2098–2106

    Article  PubMed  CAS  Google Scholar 

  • Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O’Hagan R, Pantginis J, Zhou H, Horner JW 2nd, Cordon-Cardo C, Yancopoulos GD, Depinho RA (1999) Essential role for oncogenic Ras in tumour maintenance. Nature 400:468–472

    Article  PubMed  CAS  Google Scholar 

  • Coles LC, Shaw PE (2002) PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. Oncogene 21:2236–2244

    Article  PubMed  CAS  Google Scholar 

  • Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, Rakshit S, Flannagan KS, Adsay NV, Pasca di Magliano M (2012) Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 122:639–653

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, Charles RP, Rabinovich BA, Hann B, Dankort D, Spellman PT, Phillips WA, Gray JW, Mcmahon M (2012) A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov 2:685–693

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Colvin EK, Scarlett CJ (2014) A historical perspective of pancreatic cancer mouse models. Semin Cell Dev Biol pii:S1084-9521(14)00061-5

    Google Scholar 

  • Cowley S, Paterson H, Kemp P, Marshall CJ (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852

    Article  PubMed  CAS  Google Scholar 

  • Cox AD, Der CJ (2010) Ras history: the saga continues. Small GTPases 1:2–27

    Article  PubMed  PubMed Central  Google Scholar 

  • Cuadrado A, Bruder JT, Heidaran MA, App H, Rapp UR, Aaronson SA (1993) H-ras and raf-1 cooperate in transformation of NIH3T3 fibroblasts. Oncogene 8:2443–2448

    PubMed  CAS  Google Scholar 

  • Daouti S, Higgins B, Kolinsky K, Packman K, Wang H, Rizzo C, Moliterni J, Huby N, Fotouhi N, Liu M, Goelzer P, Sandhu HK, Li JK, Railkar A, Heimbrook D, Niu H (2010) Preclinical in vivo evaluation of efficacy, pharmacokinetics, and pharmacodynamics of a novel MEK1/2 kinase inhibitor RO5068760 in multiple tumor models. Mol Cancer Ther 9:134–144

    Article  PubMed  CAS  Google Scholar 

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  • Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17:215–224

    Article  PubMed  CAS  Google Scholar 

  • Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    Article  PubMed  CAS  Google Scholar 

  • Drosten M, Dhawahir A, Sum EY, Urosevic J, Lechuga CG, Esteban LM, Castellano E, Guerra C, Santos E, Barbacid M (2010) Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J 29:1091–1104

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, Johnson NL, Granger DA, Jordan NV, Darr DB, Usary J, Kuan PF, Smalley DM, Major B, He X, Hoadley KA, Zhou B, Sharpless NE, Perou CM, Kim WY, Gomez SM, Chen X, Jin J, Frye SV, Earp HS, Graves LM, Johnson GL (2012) Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149:307–321

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova-Kovacs G, Sibilia M, Baccarini M (2009) Raf-1 addiction in Ras-induced skin carcinogenesis. Cancer Cell 16:149–160

    Article  PubMed  CAS  Google Scholar 

  • Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, Mcnamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Eser S, Reiff N, Messer M, Seidler B, Gottschalk K, Dobler M, Hieber M, Arbeiter A, Klein S, Kong B, Michalski CW, Schlitter AM, Esposito I, Kind AJ, Rad L, Schnieke AE, Baccarini M, Alessi DR, Rad R, Schmid RM, Schneider G, Saur D (2013) Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23:406–420

    Article  PubMed  CAS  Google Scholar 

  • Farrell AS, Sears RC (2014) MYC degradation. Cold Spring Harb Perspect Med 4(3):pii: a014365

    Article  Google Scholar 

  • Feig LA, Cooper GM (1988) Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol 8:3235–3243

    PubMed  CAS  PubMed Central  Google Scholar 

  • Fischmann TO, Smith CK, Mayhood TW, Myers JE, Reichert P, Mannarino A, Carr D, Zhu H, Wong J, Yang RS, Le HV, Madison VS (2009) Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. Biochemistry 48:2661–2674

    Article  PubMed  CAS  Google Scholar 

  • Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694–1703

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Flaherty KT, Puzanov I, Kim KB, Ribas A, Mcarthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, Nye E, Stamp G, Alitalo K, Downward J (2007) Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129:957–968

    Article  PubMed  CAS  Google Scholar 

  • Hatano N, Mori Y, Oh-Hora M, Kosugi A, Fujikawa T, Nakai N, Niwa H, Miyazaki J, Hamaoka T, Ogata M (2003) Essential role for ERK2 mitogen-activated protein kinase in placental Development. Genes Cells 8:847–856

    Article  PubMed  CAS  Google Scholar 

  • Hatzivassiliou G, Liu B, O’Brien C, Spoerke JM, Hoeflich KP, Haverty PM, Soriano R, Forrest WF, Heldens S, Chen H, Toy K, Ha C, Zhou W, Song K, Friedman LS, Amler LC, Hampton GM, Moffat J, Belvin M, Lackner MR (2012) ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther 11:1143–1154

    Article  PubMed  CAS  Google Scholar 

  • Hauge C, Frodin M (2006) RSK and MSK in MAP kinase signalling. J Cell Sci 119:3021–3023

    Article  PubMed  CAS  Google Scholar 

  • Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA (2003) Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res 63:5198–5202

    PubMed  CAS  Google Scholar 

  • Hoeflich KP, Gray DC, Eby MT, Tien JY, Wong L, Bower J, Gogineni A, Zha J, Cole MJ, Stern HM, Murray LJ, Davis DP, Seshagiri S (2006) Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res 66:999–1006

    Article  PubMed  CAS  Google Scholar 

  • Hofmann I, Weiss A, Elain G, Schwaederle M, Sterker D, Romanet V, Schmelzle T, Lai A, Brachmann SM, Bentires-Alj M, Roberts TM, Sellers WR, Hofmann F, Maira SM (2012) K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo. PLoS One 7:e44146

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hou J, Lam F, Proud C, Wang S (2012) Targeting Mnks for cancer therapy. Oncotarget 3:118–131

    PubMed  PubMed Central  Google Scholar 

  • Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T (2001) Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410:1111–1116

    Article  PubMed  CAS  Google Scholar 

  • Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F, Ogilvie L, Hedley D, Martin J, Marshall CJ, Springer CJ, Marais R (2004) B-RAF is a therapeutic target in melanoma. Oncogene 23:6292–6298

    Article  PubMed  CAS  Google Scholar 

  • Karreth FA, Frese KK, Denicola GM, Baccarini M, Tuveson DA (2011) C-Raf is required for the initiation of lung cancer by K-Ras(G12D). Cancer Discov 1:128–136

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Khosravi-Far R, Solski PA, Clark GJ, Kinch MS, Der CJ (1995) Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol 15:6443–6453

    PubMed  CAS  PubMed Central  Google Scholar 

  • Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH, Der CJ (1996) Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 16:3923–3933

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kolch W, Heidecker G, Lloyd P, Rapp UR (1991) Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature 349:426–428

    Article  PubMed  CAS  Google Scholar 

  • Lefloch R, Pouyssegur J, Lenormand P (2009) Total ERK1/2 activity regulates cell proliferation. Cell Cycle 8:705–711

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Takahashi M, Stork PJ (2013) Ras-mutant cancer cells display B-Raf binding to Ras that activates extracellular signal-regulated kinase and is inhibited by protein kinase A phosphorylation. J Biol Chem 288:27646–27657

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lim KH, Counter CM (2005) Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 8:381–392

    Article  PubMed  CAS  Google Scholar 

  • Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, Edwards PA, Smith PD, Cook SJ (2011) Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal 4:ra17

    PubMed  Google Scholar 

  • Malliri A, van der Kammen RA, Clark K, van der Valk M, Michiels F, Collard JG (2002) Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417:867–871

    Article  PubMed  CAS  Google Scholar 

  • Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, Kolch W (2011) Raf family kinases: old dogs have learned new tricks. Genes Cancer 2:232–260

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Moloney JB (1966) A virus-induced rhabdomyosarcoma of mice. Natl Cancer Inst Monogr 22:139–142

    PubMed  CAS  Google Scholar 

  • Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S, Long B, Liu J, Dinunzio E, Windsor W, Zhang R, Zhao S, Angagaw MH, Pinheiro EM, Desai J, Xiao L, Shipps G, Hruza A, Wang J, Kelly J, Paliwal S, Gao X, Babu BS, Zhu L, Daublain P, Zhang L, Lutterbach BA, Pelletier MR, Philippar U, Siliphaivanh P, Witter D, Kirschmeier P, Bishop WR, Hicklin D, Gilliland DG, Jayaraman L, Zawel L, Fawell S, Samatar AA (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 3:742–750

    Article  PubMed  CAS  Google Scholar 

  • Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, Mcarthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F, Auberger P, Pouyssegur J (1999) Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286:1374–1377

    Article  PubMed  CAS  Google Scholar 

  • Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, Rosen N (2009) (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA 106:4519–4524

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Qin J, Xin H, Nickoloff BJ (2012) Specifically targeting ERK1 or ERK2 kills melanoma cells. J Transl Med 10:15

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418:934

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P, Sabatier C, Mccormick F (2004) Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol Cell Biol 24:4943–4954

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Romeo Y, Zhang X, Roux PP (2012) Regulation and function of the RSK family of protein kinases. Biochem J 441:553–569

    Article  PubMed  CAS  Google Scholar 

  • Roskoski R Jr (2010) RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun 399:313–317

    Article  PubMed  CAS  Google Scholar 

  • Roskoski R Jr (2012a) ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 66:105–143

    Article  PubMed  CAS  Google Scholar 

  • Roskoski R Jr (2012b) MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem Biophys Res Commun 417:5–10

    Article  PubMed  CAS  Google Scholar 

  • Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N, Ang SL, Meloche S (2003) An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep 4:964–968

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC (1996) Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J 15:817–826

    PubMed  CAS  PubMed Central  Google Scholar 

  • Schaap D, van der Wal J, Howe LR, Marshall CJ, van Blitterswijk WJ (1993) A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. J Biol Chem 268:20232–20236

    PubMed  CAS  Google Scholar 

  • Scheffzek K, Ahmadian MR, Kabsch W, Wiesmuller L, Lautwein A, Schmitz F, Wittinghofer A (1997) The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277:333–338

    Article  PubMed  CAS  Google Scholar 

  • Scheidig AJ, Burmester C, Goody RS (1999) The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins. Structure 7:1311–1324

    Article  PubMed  CAS  Google Scholar 

  • Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD, Robertson GP (2005) Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res 65:2412–2421

    Article  PubMed  CAS  Google Scholar 

  • Shin S, Dimitri CA, Yoon SO, Dowdle W, Blenis J (2010) ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol Cell 38:114–127

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Shirasawa S, Furuse M, Yokoyama N, Sasazuki T (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260:85–88

    Article  PubMed  CAS  Google Scholar 

  • Sieben NL, Macropoulos P, Roemen GM, Kolkman-Uljee SM, Jan Fleuren G, Houmadi R, Diss T, Warren B, Al Adnani M, De Goeij AP, Krausz T, Flanagan AM (2004) In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol 202:336–340

    Article  PubMed  CAS  Google Scholar 

  • Singer G, Oldt R 3rd, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih IM (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95:484–486

    Article  PubMed  CAS  Google Scholar 

  • Slack-Davis JK, Eblen ST, Zecevic M, Boerner SA, Tarcsafalvi A, Diaz HB, Marshall MS, Weber MJ, Parsons JT, Catling AD (2003) PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol 162:281–291

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Subramanian RR, Yamakawa A (2012) Combination therapy targeting Raf-1 and MEK causes apoptosis of HCT116 colon cancer cells. Int J Oncol 41:1855–1862

    PubMed  CAS  Google Scholar 

  • Sumimoto H, Hirata K, Yamagata S, Miyoshi H, Miyagishi M, Taira K, Kawakami Y (2006) Effective inhibition of cell growth and invasion of melanoma by combined suppression of BRAF (V599E) and Skp2 with lentiviral RNAi. Int J Cancer 118:472–476

    Article  PubMed  CAS  Google Scholar 

  • Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10:842–857

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wagle N, van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, Mckenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA, Garraway LA (2014) MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 4:61–68

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • White MA, Nicolette C, Minden A, Polverino A, van Aelst L, Karin M, Wigler MH (1995) Multiple Ras functions can contribute to mammalian cell transformation. Cell 80:533–541

    Article  PubMed  CAS  Google Scholar 

  • Yao Y, Li W, Wu J, Germann UA, Su MS, Kuida K, Boucher DM (2003) Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation. Proc Natl Acad Sci USA 100:12759–12764

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, Depinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149:656–670

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yoon S, Seger R (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24:21–44

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Tikvah K. Hayes & Channing J. Der

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Tikvah K. Hayes & Channing J. Der

  3. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Channing J. Der

Authors
  1. Tikvah K. Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Channing J. Der
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Channing J. Der .

Editor information

Editors and Affiliations

  1. Max-Planck-Institute of Molecular Physiology, Dortmund, Nordrhein-Westfalen, Germany

    Alfred Wittinghofer

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Wien

About this chapter

Cite this chapter

Hayes, T.K., Der, C.J. (2014). Targeting the Raf-MEK-ERK Mitogen-Activated Protein Kinase Cascade for the Treatment of RAS Mutant Cancers. In: Wittinghofer, A. (eds) Ras Superfamily Small G Proteins: Biology and Mechanisms 1. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1806-1_6

Download citation

Publish with us

Policies and ethics

Search

Navigation