Novel therapeutic strategy for Trastuzumab resistance in HER2-overexpressing gastroesophageal adenocarcinoma.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10585
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: DEGUCHI YASUNORI 京都大学, 医学研究科, 医員 (50795581)
• Co-Investigator(Kenkyū-buntansha): 久森 重夫 京都大学, 医学研究科, 助教 (50534351) ; 小濱 和貴 京都大学, 医学研究科, 准教授 (50322649)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: HER2 / 胃癌 / 食道腺癌 / トラスツズマブ / PTEN欠失 / BEZ235

Outline of Final Research Achievements

A multicenter retrospective observational study was conducted. The study included patients who were diagnosed as advanced HER2-overexpressing gastroesophageal adenocarcinoma (GEA) and received Trastuzumab (Tmab) combined chemotherapy. Multivariate analyses demonstrated that PTEN loss could be a predictive marker of poor response to Tmab combined chemotherapy and that PTEN loss was significantly associated with poor prognosis.
PTEN knockdown impaired antiproliferative effect of Tmab in HER2-overexpressing GEA cell lines. Combination therapy of Tmab with BEZ235, PI3K/mTOR inhibitor, restored the antiproliferative effect in the PTEN knockdown/HER2-overexpressing GEA cell lines.
These results suggested that the combination therapy of Tmab with BEZ235 could be one of the promising treatment options for HER2-overexpressing GEA patients who had poor response to Tmab combined chemotherapy because of the PTEN loss.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

PTEN欠失はトラスツズマブ(Tmab)療法低感受性の指標となり、Tmabによる治療効果を期待できない患者選択のバイオマーカーになり得る。更にPTEN欠失患者では、Tmab+BEZ235の併用投与が治療選択肢の一つになる可能性が示唆されたことにより、PTEN欠失は単にTmab療法の効果不良を予測するバイオマーカーとしてだけではなく、個別化治療を受けるためのバイオマーカーとしても活用できることが期待できる。これらの結果から、HER2陽性にも関わらずTmab療法の効果が得られなかった患者の治療選択肢が広がり、HER2陽性の胃癌・食道腺癌患者の治療成績向上につながることが期待できる。