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Review article: Biomedical intelligence

Vol. 145 No. 5152 (2015)

Targeting the RAS pathway by mitogen-activated protein kinase inhibitors

  • Michael Kiessling
  • Gerhard Rogler
Cite this as:
Swiss Med Wkly. 2015;145:w14207


Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.


  1. Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nature reviews Drug discovery. 2014;13(12):928–42.
  2. Yordy JS, Muise-Helmericks RC. Signal transduction and the Ets family of transcription factors. Oncogene. 2000;19(55):6503–13.
  3. Posch C, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, et al. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Natl Acad Sci U S A. 2013;110(10):4015–20.
  4. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251‒63.
  5. Scheffzek K, Ahmadian MR, Kabsch W, Wiesmuller L, Lautwein A, Schmitz F, et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science. 1997;277(5324):333–8.
  6. Shimizu K, Goldfarb M, Suard Y, Perucho M, Li Y, Kamata T, et al. Three human transforming genes are related to the viral ras oncogenes. Proc Natl Acad Sci U S A. 1983;80(8):2112–6.
  7. COSMIC G. Catalogue of somatic mutations in cancer. 2015. Accessed August 2015.
  8. Atreya CE, Corcoran RB, Kopetz S. Expanded RAS: refining the patient population. J Clin Oncol. 2015;33(7):682–5.
  9. To MD, Wong CE, Karnezis AN, Del Rosario R, Di Lauro R, Balmain A. Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nat Genet. 2008;40(10):1240–4.
  10. Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008;40(5):600–8.
  11. Li Q, Haigis KM, McDaniel A, Harding-Theobald E, Kogan SC, Akagi K, et al. Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus. Blood. 2011;117(6):2022–32.
  12. Burd CE, Liu W, Huynh MV, Waqas MA, Gillahan JE, Clark KS, et al. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer discovery. 2014;4(12):1418–29.
  13. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919–23.
  14. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.364(26):2507–16.
  15. Mao M, Tian F, Mariadason JM, Tsao CC, Lemos R, Jr., Dayyani F, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res. 2013;19(3):657–67.
  16. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–3.
  17. Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, et al. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol. 2004;22(19):3950–7.
  18. Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004;22(8):1430–8.
  19. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.
  20. Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20(7):1965–77.
  21. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.
  22. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51.
  23. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.
  24. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–62.
  25. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nature structural & molecular biology. 2004;11(12):1192–7.
  26. Adjei A, Zhao, Y. Inhibiting MEK for Cancer Therapy. ASCO Annual Meeting. 2015.
  27. Bissonauth V, Roy S, Gravel M, Guillemette S, Charron J. Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis. Development. 2006;133(17):3429–40.
  28. Swissmedic. Cotellic®, Filmtabletten (Cobimetinibum). 2015. Accessed 07.11.2015.
  29. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.
  30. Larkin JMG, Yan Y, McArthur GA, Ascierto PA, Liszkay G, Maio M, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol 33, 2015 (suppl; abstr 9006). 2015.
  31. LoRusso PGS, Pandya SS, Kwak EL, Jones C, Belvin M, Musib LC, et al. A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 2566). 2012;2012 ASCO Annual Meeting (Abstract #2566).
  32. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773–81.
  33. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.
  34. Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res. 2008;14(1):230–9.
  35. Huynh H, Soo KC, Chow PK, Tran E. Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther. 2007;6(1):138–46.
  36. Widemann Brigitte C. LJM, Michael J. Fisher, Brian D. Weiss, AeRang Kim, Eva Dombi, Andrea Baldwin, Patricia Whitcomb, Staci Martin, Andrea Gillespie, Austin Doyle. Phase I study of the MEK1/2 inhibitor selumetinib (AZD6244) hydrogen sulfate in children and young adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas. 2014 ASCO Annual Meeting 2014;J Clin Oncol 32:5s, 2014 (suppl; abstr 10018) (Abstract number: 10018).
  37. Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16(5):1613–23.
  38. Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18(2):555–67.
  39. Catalanotti F, Solit DB, Pulitzer MP, Berger MF, Scott SN, Iyriboz T, et al. Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. Clin Cancer Res. 2013;19(8):2257–64.
  40. Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014;20(2):490–8.
  41. Tolcher AW, Khan K, Ong M, Banerji U, Papadimitrakopoulou V, Gandara DR, et al. Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin Cancer Res. 2015;21(4):739–48.
  42. Deming D.A. WRS, Sam Joseph Lubner, Daniel Mulkerin, Noelle K. LoConte, Suzanne Fioravanti, Tim Greten, et al. A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC). J Clin Oncol. 30, 2012 (suppl; abstr 3103). 2012.
  43. Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22(22):4456–62.
  44. Delord J, N. Houede, A. Awada, A. Taamma, S. J. Faivre, T. Besse-Hammer, A. Italiano, C. Vignaud, M. Donica, E. Raymond. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors. J Clin Oncol 28:15s, 2010 (suppl; abstr 2504). 2010.
  45. Van Cutsem E, Manuel Hidalgo, Igor Bazin, Jean-Luc Canon, Elena Poddubskaya, Nebojsa Manojlovic, et al. Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer. J Clin Oncol. 33, 2015 (suppl 3; abstr 344). 2015.
  46. Macarulla T, Cervantes A, Tabernero J, Rosello S, Van Cutsem E, Tejpar S, et al. Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer. Br J Cancer. 2015.
  47. Weekes CD, Von Hoff DD, Adjei AA, Leffingwell DP, Eckhardt SG, Gore L, et al. Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer. Clin Cancer Res. 2013;19(5):1232–43.
  48. Lim HY, Heo J, Choi HJ, Lin CY, Yoon JH, Hsu C, et al. A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin Cancer Res. 2014;20(23):5976–85.
  49. Long GV, Fung C, Menzies AM, Pupo GM, Carlino MS, Hyman J, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014;5:5694.
  50. Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer discovery. 2014;4(1):61–8.
  51. Villanueva J, Infante JR, Krepler C, Reyes-Uribe P, Samanta M, Chen HY, et al. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 2013;4(6):1090–9.
  52. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5.
  53. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21.
  54. Davies Barry R AL, Jennifer S. McKay PM, Samantha Steele RJ, Mark Cockerill SC, and Paul D. Smith. AZD6244 (ARRY-142886), a potent inhibitor of mitogenactivated 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. 2007;2007(6(8).
  55. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38–47.
  56. Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE, Damyanov D, Stella P, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010;5(10):1630–6.
  57. Kiessling MK, Oberholzer PA, Mondal C, Karpova MB, Zipser MC, Lin WM, et al. High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade. Blood. 2011;117(8):2433–40.
  58. Ohashi K, Sequist LV, Arcila ME, Lovly CM, Chen X, Rudin CM, et al. Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res. 2013;19(9):2584–91.
  59. Vujic I, Posch C, Sanlorenzo M, Yen AJ, Tsumura A, Kwong A, et al. Mutant NRASQ61 shares signaling similarities across various cancer types--potential implications for future therapies. Oncotarget. 2014;5(17):7936–44.
  60. Finn R.S. MMJ, B.R. Tan Jr., C.C Weekes, J.C. Bendell, A. Patnaik, G.N. Khan, et al. A Phase 1 Study of MEK Inhibitor MEK162 (ARRY-438162) in Patients with Biliary Tract Cancer. ASCO GI, Jan 19–21, 2012, San Francisco, CA. 2012.
  61. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249–56.
  62. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495–501.
  63. Kiessling MK C-FA, Samaras P, Atrott K, Cosin-Roger J, Lang S, Scharl M, Gerhard Rogler. Mutant HRAS as novel target for MEK and mTOR inhibitors. Oncotarget. 2015;published online, accessed 06.11.2015(DOI: 10.18632/oncotarget.5619).
  64. Cathcart-Rake E, Corless C, Sauer D, Lopez-Chavez A. Elderly former smoker with HRAS mutant non-small-cell lung cancer. J Thorac Oncol. 2014;9(10):e75–8.
  65. Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodere F, et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012;18(17):4806–19.

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