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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2469-2476
In Vitro and In Vivo Effects of a Farnesyltransferase Inhibitor on
Nf1-Deficient Hematopoietic Cells
Nidal Mahgoub,
Brigit R. Taylor,
Mary Gratiot,
Nancy E. Kohl,
Jackson B. Gibbs,
Tyler Jacks, and
Kevin M. Shannon
From the Department of Pediatrics, University of California, San
Francisco, CA; Department of Cancer Research; Merck and Co, West Point,
PA; and Department of Biology, Howard Hughes Medical Institute,
Massachusetts Institute of Technology, Cambridge, MA.
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.
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