A MEK inhibitor abrogates myeloproliferative disease in Kras mutant mice

Science Translational Medicine

Volumn 3, Issue 76, 2011, Pages

  Lyubynska, Natalya ^a   Gorman, Matthew F ^a   Lauchle, Jennifer O ^a,b   Hong, Wan Xing ^a   Akutagawa, Jon K ^a   Shannon, Kevin ^a   Braun, Benjamin S ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CRE RECOMBINASE; CYTOKINE; K RAS PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; RAF PROTEIN; RAS PROTEIN; BENZAMIDE DERIVATIVE; DIPHENYLAMINE; DRUG DERIVATIVE; GUANINE NUCLEOTIDE BINDING PROTEIN; HYBRID PROTEIN; KRAS2 PROTEIN, MOUSE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; MYXOVIRUS RESISTANCE PROTEINS; PROTEIN P21;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BINDING SITE; BONE MARROW CELL; CANCER GROWTH; CANCER INHIBITION; CELL DIFFERENTIATION; CELL MUTANT; CELL PROLIFERATION; CELL STIMULATION; CHRONIC MYELOMONOCYTIC LEUKEMIA; CONTROLLED STUDY; DOSE RESPONSE; DRUG BINDING; DRUG EFFECT; DRUG MECHANISM; ENZYME INHIBITION; ERYTHROID CELL; ERYTHROPOIESIS; GENE EXPRESSION; HEMATOPOIETIC STEM CELL; HUMAN; HUMAN CELL; HYPERSENSITIVITY REACTION; IN VITRO STUDY; IN VIVO STUDY; JUVENILE MYELOMONOCYTIC LEUKEMIA; LEUKOCYTE COUNT; MOUSE; MOUSE MUTANT; MYELOPROLIFERATIVE DISORDER; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SURVIVAL TIME; ANIMAL; C57BL MOUSE; DRUG ANTAGONISM; GENETICS; METABOLISM; MUTATION; NEOPLASM; PATHOLOGY; PATHOPHYSIOLOGY; RANDOMIZATION;

ANIMALS; BENZAMIDES; CELL DIFFERENTIATION; DIPHENYLAMINE; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; GTP-BINDING PROTEINS; HUMANS; MAP KINASE SIGNALING SYSTEM; MICE; MICE, INBRED C57BL; MITOGEN-ACTIVATED PROTEIN KINASE KINASES; MUTATION; MYELOPROLIFERATIVE DISORDERS; NEOPLASMS; PROTO-ONCOGENE PROTEINS P21(RAS); RAF KINASES; RANDOM ALLOCATION; RECOMBINANT FUSION PROTEINS;

EID: 79953252390     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3001069     Document Type: Article

References (27)

1. P. D. Emanuel, Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22, 1335-1342 (2008).
2. E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, D. A. Tuveson, Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243-3248 (2001).
3. B. S. Braun, D. A. Tuveson, N. Kong, D. T. Le, S. C. Kogan, J. Rozmus, M. M. Le Beau, T. E. Jacks, K. M. Shannon, Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl. Acad. Sci. U.S.A. 101, 597-602 (2004).
4. I. T. Chan, J. L. Kutok, I. R. Williams, S. Cohen, L. Kelly, H. Shigematsu, L. Johnson, K. Akashi, D. A. Tuveson, T. Jacks, D. G. Gilliland, Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J. Clin. Invest. 113, 528-538 (2004).
5. G12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. Blood 109, 3945-3952 (2007).
6. K. Rajalingam, R. Schreck, U. R. Rapp, S. Albert, Ras oncogenes and their downstream targets. Biochim. Biophys. Acta 1773, 1177-1195 (2007).
7. J. Bain, L. Plater, M. Elliott, N. Shpiro, C. J. Hastie, H. McLauchlan, I. Klevernic, J. S. Arthur, D. R. Alessi, P. Cohen, The selectivity of protein kinase inhibitors: A further update. Biochem. J. 408, 297-315 (2007).
8. A. P. Brown, T. C. Carlson, C. M. Loi, M. J. Graziano, Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother. Pharmacol. 59, 671-679 (2007).
9. J. S. Sebolt-Leopold, J. M. English, Mechanisms of drug inhibition of signalling molecules. Nature 441, 457-462 (2006).
10. J. O. Lauchle, D. Kim, D. T. Le, K. Akagi, M. Crone, K. Krisman, K. Warner, J. M. Bonifas, Q. Li, K. M. Coakley, E. Diaz-Flores, M. Gorman, S. Przybranowski, M. Tran, S. C. Kogan, J. P. Roose, N. G. Copeland, N. A. Jenkins, L. Parada, L. Wolff, J. Sebolt-Leopold, K. Shannon, Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature 461, 411-414 (2009).
11. K. Akashi, D. Traver, T. Miyamoto, I. L. Weissman, A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193-197 (2000).
12. G12D allele causes ineffective erythropoiesis in vivo. Blood 108, 2041-2044 (2006).
13. P. D. Emanuel, L. J. Bates, R. P. Castleberry, R. J. Gualtieri, K. S. Zuckerman, Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77, 925-929 (1991).
14. S. D. Barrett, A. J. Bridges, D. T. Dudley, A. R. Saltiel, J. H. Fergus, C. M. Flamme, A. M. Delaney, M. Kaufman, S. LePage, W. R. Leopold, S. A. Przybranowski, J. Sebolt-Leopold, K. Van Becelaere, A. M. Doherty, R. M. Kennedy, D. Marston, W. A. Howard Jr., Y. Smith, J. S. Warmus, H. Tecle, The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorg. Med. Chem. Lett. 18, 6501-6504 (2008).
15. R. W. Bolin, W. A. Robinson, J. Sutherland, R. F. Hamman, Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia. Cancer 50, 1683-1686 (1982).
16. H. G. Jørgensen, T. L. Holyoake, Characterization of cancer stem cells in chronic myeloid leukaemia. Biochem. Soc. Trans. 35, 1347-1351 (2007).
17. B. J. Druker, S. Tamura, E. Buchdunger, S. Ohno, G. M. Segal, S. Fanning, J. Zimmermann, N. B. Lydon, Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561-566 (1996).
18. M. A. Rieger, P. S. Hoppe, B. M. Smejkal, A. C. Eitelhuber, T. Schroeder, Hematopoietic cytokines can instruct lineage choice. Science 325, 217-218 (2009).
19. C. Dorrell, K. Takenaka, M. D. Minden, R. G. Hawley, J. E. Dick, Hematopoietic cell fate and the initiation of leukemic properties in primitive primary human cells are influenced by Ras activity and farnesyltransferase inhibition. Mol. Cell. Biol. 24, 6993-7002 (2004).
20. A. J. Sabnis, L. S. Cheung, M. Dail, H. C. Kang, M. Santaguida, M. L. Hermiston, E. Passegué, K. Shannon, B. S. Braun, Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biol. 7, e59 (2009).
21. J. Zhang, H. F. Lodish, Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 104, 1679-1687 (2004).
22. A. E. Karnoub, R. A. Weinberg, Ras oncogenes: Split personalities. Nat. Rev. Mol. Cell Biol. 9, 517-531 (2008).
23. E. Hellström-Lindberg, N. Gulbrandsen, G. Lindberg, T. Ahlgren, I. M. Dahl, I. Dybedal, G. Grimfors, E. Hesse-Sundin, M. Hjorth, L. Kanter-Lewensohn, O. Linder, M. Luthman, E. Löfvenberg, G. Oberg, A. Porwit-MacDonald, A. Rådlund, J. Samuelsson, J. M. Tangen, I. Winquist, F. Wisloff; Scandinavian MDS Group, A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colonystimulating factor: Significant effects on quality of life. Br. J. Haematol. 120, 1037-1046 (2003).
24. M. D. Trottier, M. M. Newsted, L. E. King, P. J. Fraker, Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function. Proc. Natl. Acad. Sci. U.S.A. 105, 2028-2033 (2008).
25. C. C. Zhang, H. F. Lodish, Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 103, 2513-2521 (2004).
26. C. J. Pronk, D. J. Rossi, R. Månsson, J. L. Attema, G. L. Norddahl, C. K. Chan, M. Sigvardsson, I. L. Weissman, D. Bryder, Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1, 428-442 (2007).
27. G12D mice. J.O.L. helped define pharmacokinetic and pharmacodynamic properties of PD0325901 and its toxicity in this mouse strain. W.X.H. designed and performed colony assay experiments. J.K.A. maintained mouse strains and designed and performed pharmacodynamic studies of PD0325901 using flow cytometry. K.S. was instrumental in obtaining PD0325901, aided in the design and interpretation of experiments, and provided ongoing suggestions and discussions throughout the study. B.S.B. conceived and supervised this study, was involved in the design and evaluation of all experiments, and wrote the manuscript with assistance from N.L. and K.S. Competing interests: The authors declare that they have no competing interests. J.O.L. was not affiliated with Genentech while contributing to this work.