RT Journal Article
SR Electronic
T1 Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 450
OP 461
DO 10.1158/1078-0432.CCR-12-1067
VO 19
IS 2
A1 Endo, Makoto
A1 Yamamoto, Hidetaka
A1 Setsu, Nokitaka
A1 Kohashi, Kenichi
A1 Takahashi, Yusuke
A1 Ishii, Takeaki
A1 Iida, Kei-ichiro
A1 Matsumoto, Yoshihiro
A1 Hakozaki, Michiyuki
A1 Aoki, Mikiko
A1 Iwasaki, Hiroshi
A1 Dobashi, Yoh
A1 Nishiyama, Kenichi
A1 Iwamoto, Yukihide
A1 Oda, Yoshinao
YR 2013
UL http://clincancerres.aacrjournals.org/content/19/2/450.abstract
AB Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target. Experimental Design: Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines. Results: Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro. Conclusion: mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs. Clin Cancer Res; 19(2); 450–61. ©2012 AACR.