Establishment of genomic therapy for lung cancer using comprehensive biological information

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K17763
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Kindai University
• Principal Investigator: Hamada Akira 近畿大学, 医学部, 講師 (80772954)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 肺がん / ゲノム / 網羅的生体情報 / VUS / HER2 / HER4 / EGFR / 分子標的治療

Outline of Final Research Achievements

A secondary analysis of the LUX-Lung 8 randomized trial identified the variants of unknown significance (VUS) of HER2/HER4 mutations. The HER2 and HER4 mutations were transduced into the mouse pro-B cell line to determine changes in interleukin-3 (IL-3) dependence to evaluate the transforming ability of them. As a result, only the 3 HER2 mutations E395K, G815R, and R929W showed transforming ability, suggesting that these mutations may benefit from HER2-TKI treatment. These results were reported in the journal of Lung Cancer. We also explored on-target acquired resistance mechanisms (secondary mutations) to mobocertinib, which was recently approved by the U.S. Food and Drug Administration for patients with NSCLC having in-frame insertion in exon 20 of EGFR (X20ins.), using Ba/F3 models harboring X20ins..

Free Research Field

呼吸器外科学関連

Academic Significance and Societal Importance of the Research Achievements

近年、次世代シーケンサを用いた遺伝子解析が広く用いられるようになり、既知の遺伝子異常だけでなく、臨床的意義が不明な遺伝子変異（VUS）も多数同定され、これらVUSの機能解析が求められている。本研究では、LUX-Lung 8 試験の二次解析で同定されたHER2、HER4のVUSの機能解析を、IL-3依存性細胞株である、マウスpro-B細胞株（Ba/F3細胞）に導入し、人工的な腫瘍細胞モデルを作成し評価した。その結果、3つのHER2遺伝子変異に対してHER2阻害効果のあるTKIが有効であることを明らかにし、これらの遺伝子変異を有する患者に対する治療の可能性を示した。