Signal therapy of NF1-deficient tumor xenograft in mice by the anti-PAK1 drug FK228.
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 upstream and downstream of PAK1, respectively. Here we demonstrate that (1) the anti-PAK1 drug FK228 (0.1 nM) completely blocks the growth of both NF1-deficient and NF2-deficient cancer cells in vitro, and that (2) 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.
Hirokawa
Yumiko
Y
Ludwig Institute for Cancer Research, Parkville/Melbourne, Australia.
Nakajima
Hidenori
H
Hanemann
C Oliver
CO
Kurtz
Andreas
A
Frahm
Silke
S
Mautner
Victor
V
Maruta
Hiroshi
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D047630:Depsipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D025581:Neurofibromin 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D025542:Neurofibromin 1; D025581:Neurofibromin 2; C430457:PAK1IP1 protein, human; C087123:romidepsin