Identification of alterations in non-coding RNA and development of novel therapeutic strategy for BRAF-mutated colorectal cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07169
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tohoku University
• Principal Investigator: TAKAHASHI MASANOBU 東北大学, 医学系研究科, 准教授 (00447161)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: BRAF / colorectal cancer / Mcl1

Outline of Final Research Achievements

The aim of this study was to develop Mcl1 inhibitors for patients with BRAF-mutated colorectal cancer and to identify new molecular targets for BRAF-mutated colorectal cancer. We found that Mcl1 inhibitors or siRNA-mediated knockdown of Mcl1 further enhanced cytotoxic effect by BRAF inhibitor (Hiraide S et al. Cancer Sci. 2021 112:3856-3870). We also found that retinoid the enhanced cytotoxic effect by BRAF inhibitor (we are now submitting a paper). The gene knockdown screening identified the six gene knockdown enhanced the cytotoxic effect by BRAF/MEK/EGFR inhibition (we are now submitting a paper). These new findings could lead to developing new therapeutic options for patients with BRAF-mutated cancer.

Free Research Field

臨床腫瘍学

Academic Significance and Societal Importance of the Research Achievements

BRAF変異大腸癌において、BRAF阻害薬＋MEK阻害薬＋抗EGFR抗体の併用療法群は、標準化学療法群と比べて全生存期間における優越性が第III相試験で示され、国内でも2020年に保険承認された。しかし、それでも全生存期間中央値が9ヶ月と依然予後不良であり、BRAF阻害薬＋MEK阻害薬＋抗EGFR抗体の効果増強をきたす治療法は開発されていない。
本研究から、BRAF阻害薬＋MEK阻害薬＋抗EGFR抗体の有効性をさらに高める薬剤や標的分子の候補が見いだされた。早期に臨床試験へ展開することを計画している。これらから本研究の学術的独自性と創造性は高く、がん診療においてもインパクトは高い。