journal contribution
posted on 2023-03-31, 18:11 authored by Makoto Endo, Hidetaka Yamamoto, Nokitaka Setsu, Kenichi Kohashi, Yusuke Takahashi, Takeaki Ishii, Kei-ichiro Iida, Yoshihiro Matsumoto, Michiyuki Hakozaki, Mikiko Aoki, Hiroshi Iwasaki, Yoh Dobashi, Kenichi Nishiyama, Yukihide Iwamoto, Yoshinao Oda <p>PDF file - 268K, Western blotting (WB) for p-AKT, (total) AKT, p-mTOR, (total) mTOR, p-S6RP, p-p70S6K, p-MEK1/2, and p-ERK1/2 using frozen tumor samples and corresponding normal tissue. Positive or negative staining (P: positive; N: negative) on immunohistochemistry (IHC) is shown above each band to be compared with the WB results. The expression levels in WB correspond closely to those in IHC. p-AKT, p-mTOR, and p-p70S6K show stronger expression in tumor samples than in normal tissue in both NF1-related (Case 1, 2 and 3) and sporadic (Case 4 and 5) MPNSTs, while this tendency was not apparent for p-MEK1/2 and p-ERK1/2.</p>
History
ARTICLE ABSTRACT
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.
