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Science Forum Index » Medicine - Cancer Forum » ERK inhibitor synergistic with mTOR inhibion against...
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| Steve... |
 Posted: Thu May 22, 2008 1:06 am |
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Cancer Res. 2007 Dec 1;67(23):11300-8.
Targeting protein translation in human non small cell lung cancer via
combined MEK and mammalian target of rapamycin suppression.
Legrier ME, Yang CP, Yan HG, Lopez-Barcons L, Keller SM, Pérez-Soler R,
Horwitz SB, McDaid HM.
Department of Molecular Pharmacology, Albert Einstein College of Medicine,
Bronx, New York 10461, USA.
Lung cancer is a genetically heterogeneous disease characterized by the
acquisition of somatic mutations in numerous protein kinases, including
components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling
cascades. These pathways intersect at various points, rendering this network
highly redundant and suggesting that combined mitogen-activated
protein/extracellular signal-regulated kinase (MEK) and mammalian target of
rapamycin (mTOR) inhibition may be a promising drug combination that can
overcome its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901,
in combination with the mTOR inhibitor, rapamycin, or its analogue AP23573,
exhibited dose-dependent synergism in human lung cancer cell lines that was
associated with suppression of proliferation rather than enhancement of cell
death. Concurrent suppression of MEK and mTOR inhibited ribosomal biogenesis
by 40% within 24 h and was associated with a decreased polysome/monosome
ratio that is indicative of reduced protein translation efficiency.
Furthermore, the combination of PD0325901 and rapamycin was significantly
superior to either drug alone or PD0325901 at the maximum tolerated dose in
nude mice bearing human lung tumor xenografts or heterotransplants. Except
for a PTEN mutant, all tumor models had sustained tumor regressions and
minimal toxicity. These data (a) provide evidence that both pathways
converge on factors that regulate translation initiation and (b) support
therapeutic strategies in lung cancer that simultaneously suppress the RAS
and AKT signaling network. |
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