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

Oncogene volume 36, pages 5421–5431 (2017)Cite this article

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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.

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Acknowledgements

We thank Timothy Cripe and Nancy Ratner for providing MPNST cell lines, Ahmet Hoke for providing immortalized HSC, Maureen Murphy for providing construct pWZL-Luc, Genentech for providing Frax1036, and Erica Golemis for commentary. This work was supported by grants from the NIH (RO1 CA142928), and the Children's Tumor Foundation (2011–15–012) to Jonathan Chernoff, NIH CORE Grant P30 CA006927 and an appropriation fromthe state of Pennsylvania to the Fox Chase Cancer Center. In vitro studies were supported by RSF grant 14-24-00106.

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Authors and Affiliations

  1. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    G Semenova & S M Deyev

  2. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    G Semenova, D S Stepanova & J Chernoff

  3. Russian National Research Medical University, Moscow, Russia

    D S Stepanova

  4. Biosample Repository, Fox Chase Cancer Center, Philadelphia, PA, USA

    C Dubyk

  5. Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA

    E Handorf

  6. National Research Tomsk Polytechnic University, Tomsk, Russia

    S M Deyev

  7. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A J Lazar

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  1. G Semenova
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Correspondence to J Chernoff.

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Semenova, G., Stepanova, D., Dubyk, C. et al. Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. Oncogene 36, 5421–5431 (2017). https://doi.org/10.1038/onc.2017.143

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