RRC ID 75811
Author Endo M, Yamamoto H, Setsu N, Kohashi K, Takahashi Y, Ishii T, Iida K, Matsumoto Y, Hakozaki M, Aoki M, Iwasaki H, Dobashi Y, Nishiyama K, Iwamoto Y, Oda Y.
Title Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors.
Journal Clin Cancer Res
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.
Volume 19(2)
Pages 450-61
Published 2013-1-15
DOI 10.1158/1078-0432.CCR-12-1067
PII 1078-0432.CCR-12-1067
PMID 23209032
MeSH Adolescent Adult Aged Aged, 80 and over Antineoplastic Agents / pharmacology Cell Line, Tumor Child Child, Preschool Enzyme Activation Everolimus Female Humans Infant Male Middle Aged Mitogen-Activated Protein Kinases / metabolism* Nerve Sheath Neoplasms / metabolism* Nerve Sheath Neoplasms / mortality Nerve Sheath Neoplasms / pathology Neurofibromatosis 1 / metabolism* Neurofibromatosis 1 / mortality Neurofibromatosis 1 / pathology Prognosis Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-akt / metabolism* Signal Transduction / drug effects* Sirolimus / analogs & derivatives Sirolimus / pharmacology TOR Serine-Threonine Kinases / metabolism* Young Adult
IF 10.107
Human and Animal Cells HS-Sch-2(RCB2230) HS-PSS(RCB2362) YST-1(RCB2136)