RRC ID 51817
著者 Deguchi Y, Okabe H, Oshima N, Hisamori S, Minamiguchi S, Muto M, Sakai Y.
タイトル PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma.
ジャーナル Gastric Cancer
Abstract BACKGROUND:Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as "gastroesophageal adenocarcinoma"; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA.
METHODS:Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy.
RESULTS:PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G1 cell cycle arrest were inhibited by PTEN knockdown through Akt activation in NCI-N87 and OE19 cells. PTEN knockdown impaired the antiproliferative effect of trastuzumab in OE19 xenograft models. A clinical response was observed in 50 % of PTEN-positive tumors (9 of 18) but in no tumors with PTEN loss (none of 5).
CONCLUSIONS:PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.
巻・号 20(3)
ページ 416-427
公開日 2017-5-1
DOI 10.1007/s10120-016-0627-z
PII 10.1007/s10120-016-0627-z
PMID 27517839
MeSH Adenocarcinoma / drug therapy* Adenocarcinoma / metabolism Aged Aged, 80 and over Animals Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases Drug Resistance, Neoplasm / drug effects Esophageal Neoplasms / drug therapy* Esophageal Neoplasms / metabolism Female Humans Male Mice, Nude Middle Aged Mutation PTEN Phosphohydrolase / genetics PTEN Phosphohydrolase / metabolism* Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Receptor, ErbB-2 / metabolism Stomach Neoplasms / drug therapy* Stomach Neoplasms / metabolism Trastuzumab / therapeutic use* Treatment Outcome Xenograft Model Antitumor Assays
IF 7.088
引用数 18
リソース情報
ヒト・動物細胞 MKN1(RCB1003) MKN45(RCB1001) MKN7(RCB0999) MKN74(RCB1002)