K-Ras

Reference work entry

Abstract

Mutational activations of KRas is one of the most common oncogenic events in human cancers and a heavily pursued target in therapeutic development for decades. Mutant KRas protein engages a host of signaling cascades that culminate in uncontrolled cell proliferation, enhanced survival, and set the stage for acquisition of further genetic events that propel cancer cells towards more malignant phenotypes. Direct targeting of KRas protein with inhibitors that disrupt its maturation and proper trafficking has not been successful in clinic. Instead, much attention is now focused on targeting the effector cascades that mutant KRas utilizes to exert its oncogenic feats, which include the PI3K/AKT/mTOR and Raf/MEK/ERK cascades. Numerous inhibitors targeting these pathways have been developed and are being tested in clinic. However, durable clinical success will depend on identifying effective combinations with tolerable side effects and strategies to overcome resistance mechanisms.

Keywords

Epidermal growth factor receptors (EGFRs) Farnesyl thiosalicylic acid FOLFIRI Kirsten rat sarcoma viral oncogene homolog (KRas) Anti-EGFR monoclonal antibodies Assessment Cetuximab Clinical trials Effector In human cancer mFOLFOX6 Mutations Ras GTPase activity SOS Therapeutics Tyrosine kinase inhibitor Ras GTPase-activating proteins Ras guanine nucleotide exchange factor (RasGEF) proteins Salirasib Tipifarnib Vemurafenib 

References

  1. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012;307:1383–93.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85:692–6.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ardito CM, Gruner BM, Takeuchi KK, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012;22:304–17.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Baines AT, Xu D, Der CJ. Inhibition of Ras for cancer treatment: the search continues. Future Med Chem. 2012;3:1787–808.CrossRefGoogle Scholar
  5. Barbacid M. Ras genes. Annu Rev Biochem. 1987;56:779–827.CrossRefPubMedGoogle Scholar
  6. Barbie DA, Tamayo P, Boehm JS, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462:108–12.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327:293–7.CrossRefPubMedGoogle Scholar
  8. Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:4113–20.CrossRefPubMedGoogle Scholar
  9. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521–9.CrossRefPubMedGoogle Scholar
  10. Cox AD, Der CJ. Ras family signaling: therapeutic targeting. Cancer Biol Ther. 2002;1:599–606.CrossRefPubMedGoogle Scholar
  11. da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010;116:5599–607.CrossRefPubMedGoogle Scholar
  12. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900–9.CrossRefPubMedGoogle Scholar
  13. Esteban LM, Vicario-Abejon C, Fernandez-Salguero P, et al. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol Cell Biol. 2001;21:1444–52.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Harousseau JL, Martinelli G, Jedrzejczak WW, et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009;114:1166–73.CrossRefPubMedGoogle Scholar
  15. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.CrossRefPubMedGoogle Scholar
  16. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ise K, Nakamura K, Nakao K, et al. Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene. 2000;19:2951–6.CrossRefPubMedGoogle Scholar
  18. Janne PA, Shaw AT, Pereira JR, 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;14:38–47.CrossRefPubMedGoogle Scholar
  19. Johnson L, Greenbaum D, Cichowski K, et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 1997;11:2468–81.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Johnston SR, Semiglazov VF, Manikhas GM, et al. A phase II, randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy. Breast Cancer Res Treat. 2008;110:327–35.CrossRefPubMedGoogle Scholar
  21. Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:918–27.CrossRefPubMedGoogle Scholar
  22. Koera K, Nakamura K, Nakao K, et al. K-ras is essential for the development of the mouse embryo. Oncogene. 1997;15:1151–9.CrossRefPubMedGoogle Scholar
  23. Loriot Y, Mordant P, Deutsch E, Olaussen KA, Soria JC. Are RAS mutations predictive markers of resistance to standard chemotherapy? Nat Rev Clin Oncol. 2009;6:528–34.CrossRefPubMedGoogle Scholar
  24. Luo J, Emanuele MJ, Li D, et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell. 2009;137:835–48.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.CrossRefPubMedGoogle Scholar
  26. Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22:318–30.CrossRefPubMedPubMedCentralGoogle Scholar
  27. O’Byrne KJ, Gatzemeier U, Bondarenko I, et al. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol. 2011;12:795–805.CrossRefPubMedGoogle Scholar
  28. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Rao S, Cunningham D, de Gramont A, 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;22:3950–7.CrossRefPubMedGoogle Scholar
  30. Riely GJ, Johnson ML, Medina C, et al. A phase II trial of Salirasib in patients with lung adenocarcinomas with KRAS mutations. J Thorac Oncol. 2011;6:1435–7.CrossRefPubMedGoogle Scholar
  31. Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. Understanding Ras: ‘it ain’t over ‘til it’s over’. Trends Cell Biol. 2000;10:147–54.CrossRefPubMedGoogle Scholar
  32. Sparano JA, Moulder S, Kazi A, et al. Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB–IIIC breast cancer. Clin Cancer Res. 2009;15:2942–8.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Umanoff H, Edelmann W, Pellicer A, Kucherlapati R. The murine N-ras gene is not essential for growth and development. Proc Natl Acad Sci USA. 1995;92:1709–13.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 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. 2004;22:1430–8.CrossRefPubMedGoogle Scholar
  35. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.CrossRefPubMedGoogle Scholar
  36. Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31:1931–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Washington University School of MedicineSaint LouisUSA

Personalised recommendations