Signal therapy of NF1-deficient tumor xenograft in mice by the anti-PAK1 drug FK228
Volume 4, Issue 4
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Pages 385 - 387http://dx.doi.org/10.4161/cbt.4.4.1649
Authors: Yumiko Hirokawa, C. Oliver Hanemann, Andreas Kurtz, Silke Frahm, Victor Mautner and Hiroshi Maruta View affiliations
PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for the malignant growth of RAS transformants as well as both NF1-deficient and NF2-deficient cancer cells. FK228, a histone deacetylase (HDAC) inhibitor, suppresses the growth of more than 70% of human cancers in vivo including RAS transformants, breast cancers and prostate cancers by activating a set of genes including the tumor suppressors gelsolin and p21/WAF1, that block up-stream and down-stream of PAK1, respectively. Here we demonstrate that (i) the anti-PAK1 drug FK228 (0.1 nM) completely blocks the growth of both NF1-deficient and NF2-deficent cancer cells in vitro, and that (ii) FK228 (2.5 mg/kg, i.p., twice a week) causes the complete regression of an NF1-deficient human malignant peripheral nerve sheath tumor (MPNST) xenograft in nude mice. This is the very first case where a chemical drug in clinical trials for cancers has ever worked so effectively on neurofibromatosis (experimental neurofibromas) in vivo.