Overcoming drug resistance to refractory ovarian clear cell adenocarcinoma with focusing on DNA repair abnormality

2014 Fiscal Year Final Research Report

• Project/Area Number: 25670705
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Nara Medical University
• Principal Investigator: AKASAKA Juria 奈良県立医科大学, 医学部, 助教 (90526724)
• Co-Investigator(Kenkyū-buntansha): YOSHIMOTO Chiharu 奈良県立医科大学, 医学部, 助教 (00526725) ; OI Hidekazu 近畿大学, 医学部附属病院, 教授 (10283368) ; YOSHIDA Shozo 奈良県立医科大学, 医学部, 講師 (40347555) ; FURUKAWA Naoto 奈良県立医科大学, 医学部, 講師 (50347556)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 卵巣明細胞腺癌 / HNF-1β / Chk1 / Claspin / チェックポイント / 婦人科腫瘍

Outline of Final Research Achievements

We have found that transcription factor HNF-1β expressed in clear cell adenocarcinoma induced hyperphosphorylation of Chk1 acting on DNA damage checkpoint, leading to acquisition of anticancer drug resistance. Chk1 is activated through the signals from ATM/ATR which recognize damaged DNA sites. Despite knockdown of these proteins, hyperphosphorylation of Chk1 was maintained. With focusing on Claspin, which can form a complex with Chk1 and facilitate its activation, it was found that HNF-1β activated autophosphorylation of Chk1 through the induction of Claspin expression. Accordingly, knockdown of Claspin led to improvement in sensitivity to anticancer drugs. The Clapsin-Chk1 complex was shown to be a novel therapeutic target in the clear cell adenocarcinoma.

Free Research Field

産婦人科