Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis

G. Semenova, D. S. Stepanova, C. Dubyk, E. Handorf, S. M. Deyev, A. J. Lazar, J. Chernoff

Research output: Contribution to journalArticle

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Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are devastating sarcomas for which no effective medical therapies are available. Over 50% of MPSNTs are associated with mutations in NF1 tumor suppressor gene, resulting in activation of Ras and its effectors, including the Raf/Mek/Erk and PI3K/Akt/mTORC1 signaling cascades, and also the WNT/β-catenin pathway. As Group I p21-activated kinases (Group I Paks, PAK1/2/3) have been shown to modulate Ras-driven oncogenesis, we asked if these enzymes might regulate signaling in MPNSTs. In this study we found a strong positive correlation between the activity of PAK1/2/3 and the stage of human MPNSTs. We determined that reducing Group I Pak activity diminished MPNST cell proliferation and motility, and that these effects were not accompanied by significant blockade of the Raf/Mek/Erk pathway, but rather by reductions in Akt and β-catenin activity. Using the small molecule PAK1/2/3 inhibitor Frax1036 and the MEK1/2 inhibitor PD0325901, we showed that the combination of these two agents synergistically inhibited MPNST cell growth in vitro and dramatically decreased local and metastatic MPNST growth in animal models. Taken together, these data provide new insights into MPNST signaling deregulation and suggest that co-targeting of PAK1/2/3 and MEK1/2 may be effective in the treatment of patients with MPNSTs.Oncogene advance online publication, 22 May 2017; doi:10.1038/onc.2017.143.

Original languageEnglish
JournalOncogene
DOIs
Publication statusAccepted/In press - 22 May 2017

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p21-Activated Kinases
Neurilemmoma
Neoplasm Metastasis
Growth
Catenins
Tumor Suppressor Genes
Phosphatidylinositol 3-Kinases
Oncogenes
Sarcoma
Cell Movement
Publications
Carcinogenesis
Animal Models
Cell Proliferation
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. / Semenova, G.; Stepanova, D. S.; Dubyk, C.; Handorf, E.; Deyev, S. M.; Lazar, A. J.; Chernoff, J.

In: Oncogene, 22.05.2017.

Research output: Contribution to journalArticle

Semenova, G. ; Stepanova, D. S. ; Dubyk, C. ; Handorf, E. ; Deyev, S. M. ; Lazar, A. J. ; Chernoff, J. / Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. In: Oncogene. 2017.
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