Targeting DNA damage response in breast cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16869
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kyushu University
• Principal Investigator: Shigechi Tomoko (高居智子) 九州大学, 大学病院, 学術研究員 (10818090)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: PARP / BRCA１変異陽性乳がん / 相同組み換え修復 / PARP阻害剤耐性 / DNA損傷チェックポイント機構 / BRCA遺伝子変異

Outline of Final Research Achievements

PARP inhibitors (PARPis) are a type of targeted therapy for BRCA1/2-deficient cancers, but their efficacy is limited by drug resistance. Therefore, overcoming this problem is paramount importance for improving treatment efficacy. BRCA1 is crucial for multiple biological processes, including homologous recombination repair. ATR directly phosphorylates BRCA1 in response to damaged DNA which is required for cell-cycle checkpoints.
Here, we tried to establish of PARPi-resistant cell line from BRCA1-deficient breast cancer cell line to investigate the mechanisms of PARPi resistance. The BRCA1-deficient breast cancer cell line with pre-existing PARPi-resistant was sensitive to ATRi. Thus, it is suggested that ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA1-deficient cancers.

Free Research Field

乳癌

Academic Significance and Societal Importance of the Research Achievements

本邦でもBRCA変異陽性乳がんに対するPARP阻害剤（olaparib）の適応拡大が承認され、この薬剤の有効性に期待が高まる一方で、近い将来に耐性の問題が実臨床での大きな障害となることが予想される。
本研究は、BRCAを中心とする相同組み換え修復とDNA損傷チェックポイント機構を含むDNA損傷応答修復経路を標的とする乳がんの新規治療法の確立を目指しており、最終的には、BRCA遺伝子変異陽性乳がんのPARP阻害剤耐性克服に限らず、その他の相同組み換え修復遺伝子異常を有する乳がん治療法の開発への応用も可能であると考えられる。