2023 Fiscal Year Final Research Report
Overcoming treatment resistance based on metabolic properties of EGFR gene mutations
| Project/Area Number |
21K08191
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 53030:Respiratory medicine-related
|
|---|
| Research Institution | Kawasaki Medical School |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
越智 宣昭 川崎医科大学, 医学部, 講師 (80611615)
山根 弘路 川崎医科大学, 医学部, 准教授 (50624897)
中西 秀和 川崎医科大学, 医学部, 准教授 (50309548)
|
|---|
| Project Period (FY) |
2021-04-01 – 2024-03-31
|
| Keywords | EGFR / ALK / 薬剤耐性 / 代謝 |
|---|
| Outline of Final Research Achievements |
We compared various EGFR gene mutant cell lines using multi-omics analysis and discovered the proteins, genes, and metabolic pathways that serve as the basis for treatment strategies specific to each EGFR mutation. SLC1A3, which is involved in glutamate transport, is highly expressed in EGFR inhibitor-resistant cells, suggesting the possibility of overcoming resistance with its inhibitor or glutaminase inhibitor. Single cell analysis showed immune-related signal and DNA metabolic changes upon exposure to an EGFR inhibitor. In addition, high SOD1 expression was observed in an ALK-mutant cell line resistant to an ALK inhibitor (alectinib), suggesting that this inhibition may overcome resistance. It is hoped that these findings would lead to further therapeutic effects of molecular targeted drugs.
|
| Free Research Field |
肺癌
|
| Academic Significance and Societal Importance of the Research Achievements |
EGFR変異あるいはALK変異を有する進行非小細胞肺癌は、EGFRあるいはALKのチロシンキナーゼ阻害薬の導入により劇的な効果がもたらされてきたが、治癒に至ることは極めて稀である。EGFR変異の違いによる阻害薬の効果の差や耐性を誘導する機序は不明の部分が多く、それを解明する手法としてプロテオーム解析、トランスクリプトーム解析、メタボローム解析、およびシングルセル解析を用いて基礎研究を行った。その結果、グルタチオン、グルタミン、および活性酸素の分解酵素などの新たな標的を発見し、耐性克服のためにそれら阻害薬の有用性を前臨床試験として証明することができた。今後は臨床応用すべく本研究をさらに進めたい。
|
