K-ras Inhibitors and Pancreatic Cancer

  • Steven R. Alberts
Part of the M. D. Anderson Solid Tumor Oncology Series book series (MDA)

The ras family includes a group of five guanosine triphosphate-binding proteins (H-ras, K-ras, M-ras, N-ras, and R-ras). In mammals ras-proto-oncogenes encode for four related and highly conserved proteins, H-ras, N-ras, K-ras 4A, and K-ras 4B (1). Ras proteins serve as important components of signaling pathways involved in a variety of cellular functions, including cell cycle control, cell adhesion, endocytosis, exocytosis, and apoptosis. In order for these proteins to perform their functions they need to bind guanosine triphosphate (GTP) (2). Guanosine triphosphate creates a conformational change allowing ras to attach more tightly to its intended target. Hydrolysis of GTP to guanosine diphosphate (GDP) inactivates ras. The ability of ras to exchange GDP for GTP is under the control of guanine nucleotide exchange factors (GEFs). The GEFs are activated by growth factors or cytokines and promote the release of GDP and therefore the binding of GTP. GTPase-activating proteins (GAPs) return ras to its inactive state.

Although a variety of genetic modifications have been identified in pancreatic carcinoma, mutations of K-ras are by far the most commonly occurring mutation. Mutations are seen in >85% of pancreatic ductal carcinomas ( 3 ). The development of mutations in K-ras appear early in the development of pancreatic cancer, having been observed in precursor lesions within the pancreatic duct ( 4 ). The mutations in K-ras in pancreatic cancer are also unique in that it typically involves codon 12, but may also rarely involve codons 13 or 61 ( 5, 6 ). These mutations in K-ras make it resistant to GAP and as a result lead to constitutive activation of downstream pathways, resulting in altered regulation of cellular proliferation. In preclinical studies, using the pancreatic cancer cell lines Panc-1 and MiaPaca-2, blocking activated K-ras resulted in increased apoptosis and loss of other malignant features supporting a pivotal role for K-ras in the development and maintenance the malignant phenotype.

Based on the frequency and apparent critical role of K-ras in pancreatic cancer several approaches have been developed to block activated K-ras. This includes both farnesyl transferase inhibitors and antisense oligonucleotides.


Pancreatic Cancer Clin Oncol Antisense Oligonucleotide Advanced Pancreatic Cancer Rous Sarcoma Virus 
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  1. 1.
    Lowy DR, Williamson BM. 1993, Function and regulation of ras. Annu Rev Biochem 62:851–891.CrossRefPubMedGoogle Scholar
  2. 2.
    Wittinghofer A, Scheffzek K, Ahmadian MR. 1997, The interaction of Ras with GTPase-activating proteins. FEBS Letts 410:63–67.CrossRefGoogle Scholar
  3. 3.
    Rozenblum E, Schutte M, Goggins M, 1997, Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 57:1731–1734.PubMedGoogle Scholar
  4. 4.
    Moskaluk CA, Hruban RH, Kern SE. 1997, p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57:2140–2143.PubMedGoogle Scholar
  5. 5.
    Sakorafas GH. 1999, Pancreatic cancer. In: Kurzrock R, Talpaz M (eds.) Molecular biology in cancer medicine, 2nd ed. London, Martin Dunitz Ltd, 393–409.Google Scholar
  6. 6.
    Bos JL. 1989, ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689.PubMedGoogle Scholar
  7. 7.
    Kato K, Cox AD, Hisaka MM, et al. 1992, Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci USA 89:6403–6407.CrossRefPubMedGoogle Scholar
  8. 8.
    Sepp-Lorenzino L, Ma Z, Rands E, et al. 1995, A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 55:5302–5309.PubMedGoogle Scholar
  9. 9.
    Moasser MM, Sepp-Lorenzino L, Kohl NE, et al. 1998, Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Natl Acad Sci U S A 95: 1369–1374.CrossRefPubMedGoogle Scholar
  10. 11.
    Liu M, Bryant MS, Chen J, et al. 1998, Antitumor activity of SCH 66336, an orally bioavaila-ble tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 58:4947–4956.PubMedGoogle Scholar
  11. 12.
    Adjei AA, Erlichman C, Davis JN, et al. 2000, A phase I trial of the farnesyl transferase inhibitor SCH66336: Evidence for biological and clinical activity. Cancer Res 60:1871–1877.PubMedGoogle Scholar
  12. 13.
    Awada A, Eskens F, Piccart M, et al. 2002, Phase I and pharmacological study of the oral far-nesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours. Eur J Cancer 38:2272–2278.CrossRefPubMedGoogle Scholar
  13. 14.
    Eskens F, Awada A, Cutler DL, et al. 2001, Phase I and pharmacokinetic study of the oral far-nesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors. J Clin Oncol 19:1167–1175.PubMedGoogle Scholar
  14. 15. Hurwitz H, Amado R, Prager D, et al. 2000, Phase I trial of the farnesyl transferase inhibitor SCH66336 plus gemcitabine in advanced cancers (abstract 717). Proc Am Soc Clin Oncol, 185a.Google Scholar
  15. 16.
    Venet M, End D, Angibaud P. et al. 2003, Farnesyl protein transferase inhibitor ZARNESTRA R115777—history of a discovery. Curr Top Med Chem 3:1095–1102.CrossRefPubMedGoogle Scholar
  16. 17.
    End DW, Smets G, Todd AV, et al. 2001, Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61: 131–137.PubMedGoogle Scholar
  17. 18.
    Crul M, Klerk GJ, de Swart M, et al. 2002, Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 20: 2726–2735.CrossRefPubMedGoogle Scholar
  18. 19.
    Lara PN, Jr., Law LY, Wright JJ, et al. 2005, Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium Trial. Anti-Cancer Drugs 16:317–321.CrossRefPubMedGoogle Scholar
  19. 20.
    Zujewski J, Horak ID, Bol CJ, et al. 2000, Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 18: 927–941.PubMedGoogle Scholar
  20. 21.
    Punt CJ, van Maanen L, Bol CJ, et al. 2001, Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors. Anti-Cancer Drugs 12:193–197.CrossRefPubMedGoogle Scholar
  21. 22.
    Patnaik A, Eckhardt SG, Izbicka E, et al. 2003, A phase I, pharmacokinetic, and biological study of the farnesyltransferase inhibitor tipifarnib in combination with gemcitabine in patients with advanced malignancies. Clin Cancer Res 9:4761–4771.PubMedGoogle Scholar
  22. 23.
    Cohen SJ, Ho L, Ranganathan S, et al. 2003, Phase II and pharmacodynamic study of the far-nesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 21:1301–1306.CrossRefPubMedGoogle Scholar
  23. 24.
    Macdonald JS, McCoy S, Whitehead RP, et al. 2005, A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs 23:485–487.CrossRefPubMedGoogle Scholar
  24. 25.
    Van Cutsem E, van de Velde H, Karasek P, et al. 2004, Phase III trial of gemcitabine plus tipi-farnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430–1438.CrossRefPubMedGoogle Scholar
  25. 26.
    Lobell RB, Liu D, Buser CA, et al. 2002, Preclinical and clinical pharmacodynamic assess-ment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther 1:747–758.PubMedGoogle Scholar
  26. 27.
    Martin NE, Brunner TB, Kiel KD, et al. 2004, A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clin Cancer Res 10:5447–5454.CrossRefPubMedGoogle Scholar
  27. 28.
    Wacheck V, Zangemeister-Wittke U. 2006, Antisense molecules for targeted cancer therapy. Crit Rev Oncol Hematol 59:65–73.CrossRefPubMedGoogle Scholar
  28. 29.
    Phillips MI. 2005, Antisense therapuetics: a promise waiting to be fulfilled. In: Phillips MI (ed.) Antisense therapeutics, 2nd ed. Totowa, Humana Press NJ, 3–10.Google Scholar
  29. 30.
    Makeyev AV, Eastmond DL, Liebhaber SA. 2002, Targeting a KH-domain protein with RNA decoys. RNA 8:1160–1173.CrossRefPubMedGoogle Scholar
  30. 31.
    Mizuno T, Chou MY, Inouye M. 1984, A unique mechanism regulating gene expression: Translational inhibition by a complementary RNA transcript (micRNA). Proc Natl Acad Sci USA 81:1966–1970.CrossRefPubMedGoogle Scholar
  31. 32.
    Stephenson ML, Zamecnik PC. 1978, I nhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci U S A 75: 285–288.CrossRefPubMedGoogle Scholar
  32. 33.
    Zamecnik PC, Stephenson ML. 1978, I nhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A 75:280–284.CrossRefPubMedGoogle Scholar
  33. 34.
    Couzin J. 2002, Small RNAs make big splash. Science 298:2296–2297.CrossRefPubMedGoogle Scholar
  34. 35.
    Boyer DS, Cowen SJ, Danis RP, et al. 2002, Randomized dose-comparison studies of intravitreous fomivirsen for treatment of cytomegalovirus retinitis that has reactivated or is persistently active despite other therapies in patients with AIDS. Am J Ophthalmol 133:475–483.CrossRefGoogle Scholar
  35. 36.
    Nakada Y, Saito S, Ohzawa K, et al. 2001, Antisense oligonucleotides specific to mutated K-ras genes inhibit invasiveness of human pancreatic cancer cell lines. Pancreatology 1:314–319.CrossRefPubMedGoogle Scholar
  36. 37.
    Kita K, Saito S, Morioka CY, et al. 1999, Growth inhibition of human pancreatic cancer cell lines by anti-sense oligonucleotides specific to mutated K-ras genes. Int J Cancer 80:553–558.CrossRefPubMedGoogle Scholar
  37. 38.
    Ohnami S, Matsumoto N, Nakano M, et al. 1999, Identification of genes showing differential expression in antisense K-ras-transduced pancreatic cancer cells with suppressed tumorigenicity. Cancer Res 59:5565–5571.PubMedGoogle Scholar
  38. 39.
    Cowsert LM. 1997, In vitro and in vivo activity of antisense inhibitors of ras: potential for clinical development. Anti-Cancer Drug Design 12:359–371.PubMedGoogle Scholar
  39. 40.
    Chen G, Oh S, Monia BP, et al. 1996, Antisense oligonucleotides demonstrate a dominant role of c-Ki-RAS proteins in regulating the proliferation of diploid human fibroblasts. J Biol Chem 271:28259–28265.CrossRefPubMedGoogle Scholar
  40. 41.
    Cunningham CC, Holmlund JT, Geary RS, et al. 2001, A Phase I trial of H-ras antisense oli-gonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma. Cancer 92:1265–1271.CrossRefPubMedGoogle Scholar
  41. 42.
    Gordon GS, Sandler AB, Holmlund JT, et al. 1999, A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, administered by a 24-hour (hr) weekly infusion in patients (pts) with advanced cancer (abstract 604). J Clin Oncol 18: 157a.Google Scholar
  42. 43.
    Adjei AA, Dy GK, Erlichman C, et al. 2003, A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin Cancer Res 9:115–123.PubMedGoogle Scholar
  43. 44.
    Alberts SR, Schroeder M, Erlichman C, et al. 2004, Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. J Clin Oncol 22:4944–4950.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Steven R. Alberts
    • 1
  1. 1.Division of Medical OncologyMayo Clinic College of MedicineRochesterUSA

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