2018 Fiscal Year Final Research Report

CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors

Research Project

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Project/Area Number	16H05311
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Respiratory organ internal medicine
Research Institution	National Cancer Center Japan
Principal Investigator	Genichiro Ishii 国立研究開発法人国立がん研究センター, 先端医療開発センター, 分野長 (00270869)
Co-Investigator(Kenkyū-buntansha)	菅野雅人国立研究開発法人国立がん研究センター, 東病院, 医長 (40643606) 石橋昌幸国立研究開発法人国立がん研究センター, 東病院, レジデント (80763630)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	がん関連線維芽細胞 / 肺腺癌 / EGFR-TKI / 薬剤感受性 / がん微小環境
Outline of Final Research Achievements	Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential. Immunohistochemical analysis revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.
Free Research Field	呼吸器内科学
Academic Significance and Societal Importance of the Research Achievements	実臨床面では、本分子機構を応用することにより、EGFR-TKIに対する初回治療感受性を劇的に増強することが可能となる。すなわち、今まで以上に、EGFR-TKIに対するスーパーレスポンダー（極めて著効する症例）を増やすことが出来る可能性がある。尚、本申請に関する研究は申請者独自の発見であり、企業アカデミア連携で最終製品の権利化が可能である。その分子　機構が解明されれば、学問的、臨床的価値は極めて高い。