In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells.
Oncogenic RAS alleles encode proteins that accumulate in the guanosine triphosphate (GTP)-bound state. Because post-translational processing of Ras by farnesyltransferase is essential for biologic function, inhibitors of this enzyme have been developed as rational cancer therapeutics. We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene. Nf1 encodes a GTPase activating protein for Ras, and Nf1-deficient (Nf1-/-) hematopoietic cells show hyperactive Ras signaling through the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibited H-Ras prenylation in cell lines and in primary hematopoietic cells and abrogated the in vitro growth of myeloid progenitor colonies in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also partially blocked GM-CSF-induced MAP kinase activation, but did not reduce constitutively elevated levels of MAP kinase activity in primary Nf1-/- cells. Injection of a single dose of 40 or 80 mg/kg of L-744, 832 increased the amount of unprocessed H-Ras in bone marrow cells, but had no detectable effect on N-Ras. Adoptive transfer of Nf1-/- hematopoietic cells into irradiated mice induces a myeloproliferative disorder that did not respond to L-744,832 treatment. We speculate that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ras processing to inhibition by this FTI.
Mahgoub
N
N
Department of Pediatrics, University of California, San Francisco, CA, USA.
Taylor
B R
BR
Gratiot
M
M
Kohl
N E
NE
Gibbs
J B
JB
Jacks
T
T
Shannon
K M
KM
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003433:Crosses, Genetic; D051231:Farnesyltranstransferase; D005260:Female; D016147:Genes, Tumor Suppressor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007951:Leukemia, Myeloid; D007958:Leukocyte Count / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000196:embryology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D025542:Neurofibromin 1; D017368:Protein Prenylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; C096898:L 744832; D025542:Neurofibromin 1; D011506:Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins