The investigation in synthetic lethal effect of CCNE1 for ARID1A mutation in ovarian clear cell carcinoma

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16819
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Nara Medical University
• Principal Investigator: Kawahara Naoki 奈良県立医科大学, 医学部, 助教 (70623495)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 卵巣癌 / 明細胞癌 / 合成致死 / ARID1A遺伝子変異 / Cyclin-E1 / CCNE1

Outline of Final Research Achievements

Ovarian clear cell carcinoma (OCCC) is resistant to platinum chemotherapy and is characterized by poor prognosis. We conducted siRNA screening to identify synthetic lethal candidates for the ARID1A mutation; as a result, we identified Cyclin-E1 (CCNE1) as a potential target that affects cell viability. To further clarify the effects of CCNE1, human OCCC cell lines, namely TOV-21G and KOC7c (ARID1A mutant lines), and RMG-I and ES2 (ARID1A wild type lines) were transfected with siRNA targeting CCNE1 or a control vector. Loss of CCNE1 reduced proliferation of the TOV-21G and KOC7c cells but not of the RMG-I and ES2 cells. Furthermore, in vivo interference of CCNE1 effectively inhibited tumor cell proliferation in a xenograft mouse model. This study showed for the first time that CCNE1 is a synthetic lethal target gene to ARID1A-mutated OCCC. Targeting this gene may represent a putative, novel, anticancer strategy in OCCC treatment.

Free Research Field

卵巣癌

Academic Significance and Societal Importance of the Research Achievements

卵巣明細胞癌は既存の化学療法に抵抗性であり予後不良という特徴がある。今日、合成致死戦略に基づきPARP阻害剤が開発され、高異型度漿液性癌に特徴的な相同組換修復異常を持つ卵巣癌の場合には高い治癒率を誇るが、卵巣明細胞癌においては効果が乏しいのが現状である。更に上皮性卵巣癌に占める明細胞癌の割合は欧米では6-8%と低いものの、本邦では25％以上と高い割合を占めており、本邦においては卵巣明細胞癌を標的とした新たな治療戦略の構築が求められている。我々は卵巣明細胞癌の約半数が変異していると報告されているARID1A遺伝子変異に特異的に効果を発揮する治療ターゲットを同定し効果とメカニズムを明らかにした。