Studies on the mechanism of action of antibody-drug conjugates in EGFR mutation-positive lung cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07100
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyushu University
• Principal Investigator: Iwama Eiji 九州大学, 大学院医学研究院呼吸器内科学分野, 准教授 (40567343)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 抗体薬物複合体 / 非小細胞肺癌 / EGFR遺伝子変異 / ダイマー / 耐性克服

Outline of Final Research Achievements

In this study, we found that: 1) the expression of EGFR-HER2 heterodimer formation was higher in EGFR mutation-positive lung cancer cell lines than in EGFR wild-type cells; 2) in cells without HER2 amplification, almost all of the internalized HER2 in cells without HER2 amplification coexisted with EGFR; 3)internalized HER2 in EGFR mutation-positive cells was rapidly transported to lysosomes; 4) The anti-HER2 antibody-drug conjugate trastuzumab emtansine (T-DM1) was effective in EGFR mutation-positive lung cancers, sensitivity to T-DM1 was high and this sensitivity was maintained in cell lines after osimertinib resistance. These findings indicate that the formation of numerous HER2-EGFR heterodimers in EGFR mutation-positive lung cancers increases the sensitivity to T-DM1 by increasing EGFR-mediated uptake of HER2 into the cytoplasm and lysosomes, and that anti HER2 antibody-drug conjugates could be a new therapeutic strategy for EGFR mutation-positive lung cancer.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

EGFR遺伝子変異陽性肺癌に対するEGFR-TKI耐性に関するこれまでの報告は、その細胞内シグナル伝達の解明、阻害に関するものが主体であり、変異型EGFRの細胞内動態と抗体薬物複合体の効果に着目した研究は認めなかった。本研究において、EGFR遺伝子変異陽性肺癌におけるEGFR-HER2ヘテロダイマーの細胞内動態を明らかにするとともに、HER2に対する抗体薬物複合体の作用機序を明らかにし学会、論文報告を行った。これらの結果はEGFR遺伝子変異陽性肺癌を含む様々ながん種に対する抗体薬物複合体開発の一助になると考えられ、学術的、社旗的意義の高い研究と考えられる。