Exploration of predictive molecular biomarkers for acquired resistance mechanisms to EGFR tyrosine kinase inhibitors

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K07336
• 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: Kindai University
• Principal Investigator: Suda Kenichi 近畿大学, 医学部, 講師 (30631593)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: EGFR遺伝子変異 / 肺腺がん / 分子標的治療薬 / 獲得耐性 / tumor heterogeneity

Outline of Final Research Achievements

During the study period, we could not identify pre-treatment molecular biomarkers that predicts the acquired resistance mechanisms to EGFR-tyrosine kinase inhibitors (TKIs). However, we observed that the mechanisms by which cancer cells survive in the early stage of EGFR-TKI exposure differs depending on the type of TKI, and that RYK is one of the mechanisms. We also examined inter-tumor heterogeneity of acquired resistance mechanisms to EGFR-TKIs in the same patients. We observed that two different resistance mechanisms have developed, depending on the metastatic sites, in about half of the patients.
In addition, during the study period, several novel molecular-targeted agents have been developed for lung cancers with MET exon 14 skipping mutation, KRAS G12C mutation, EGFR and HER2 exon 20 insertion mutations (and some have been already approved for clinical use), therefore, we also explored acquired resistance mechanisms to these agents.

Free Research Field

外科腫瘍学

Academic Significance and Societal Importance of the Research Achievements

EGFR遺伝子変異のある肺がん（本邦では肺腺がんの約半数を占めるとされている）において、第一選択の薬物療法はEGFRキナーゼ阻害剤（EGFR-TKI）である。EGFR-TKIは著明な臨床効果を示すが、約1～2年以内に薬剤耐性が出現し、その耐性機序は多岐にわたることが報告されている。本研究では、①耐性機序を治療開始前のバイオマーカーで予測可能か、②（耐性獲得前の）EGFR-TKI治療早期にがん細胞が生き残るメカニズム、③同一患者内の異なる病巣で耐性機序が異なる場合があるか、ある場合はその頻度、についての検討を通して、獲得耐性を克服するために必要な基礎データを創出した。