N. Mahgoub et al., In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells, BLOOD, 94(7), 1999, pp. 2469-2476
Oncogenic RAS alleles encode proteins that accumulate in the guanosine trip
hosphate (GTP)-bound state. Because post-translational processing of Pas by
farnesyltransferase is essential for biologic function, inhibitors of this
enzyme have been developed as rational cancer therapeutics. We have invest
igated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine m
odel of myeloid leukemia that is associated with inactivation of the Nf1 tu
mor suppressor gene. Nf1 encodes a GTPase activating protein for Pas, and N
f1-deficient (Nf1-/-) hematopoietic cells show hyperactive Pas signaling th
rough the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibit
ed H-Ras prenylation in cell lines and in primary hematopoietic cells and a
brogated the in vitro growth of myeloid progenitor colonies in response to
granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also pa
rtially blocked GM-CSF-induced MAP kinase activation, but did not reduce co
nstitutively 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 a
mount of unprocessed H-Ras in bone marrow cells, but had no detectable effe
ct on N-Ras, Adoptive transfer of Nf1-/- hematopoietic cells into irradiate
d 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,
(C) 1999 by The American Society of Hematology.