Effects of molecular-targeted drugs on nonsmoking-related lung cancer models

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591182
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kawasaki Medical School
• Principal Investigator: TAKIGAWA Nagio 川崎医科大学, 医学部, 教授 (60325107)
• Co-Investigator(Kenkyū-buntansha): KIURA Katsuyuki 岡山大学, 大学病院, 教授 (10243502) ; YAMANE Hiromichi 川崎医科大学, 医学部, 准教授 (50624897) ; TABAYASHI Takayuki 埼玉医科大学, 医学部, 講師 (60624898) ; OCHI Nobuaki 川崎医科大学, 医学部, 講師 (80611615)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: EGFR / mTOR / JAK2 / STAT3 / 肺癌 / 薬剤耐性 / 遺伝子改変マウス / 血管新生

Outline of Final Research Achievements

EGFR mutations are more frequently observed in non-smokers and adenocarcinoma patients. The majority of EGFR mutant lung cancers initially sensitive to EGFR-TKI become resistant to these agents within 1 year. To overcome EGFR-TKI resistance mechanisms, we have studied using EGFR-TKI resistant lung cancer cell lines, xenograft models, and EGFR-transgenic mice. mTOR inhibitor,　JAK2/STAT3 inhibitor, and EGFR/VEGFR dual inhibitor were all effective. Next, second-generation EGFR-TKI, afatinib, was more potent than gefitinib and the combination of afatinib with bevacizumab efficiently suppressed resistant tumors. Furthermore, we established a novel gefitinib-resistant lung cancer cell line and found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated, dual inhibition of EGFR and SRC restored gefitinib sensitivity. In conclusion, our results indicate that the molecular target drugs may be a potent strategy to overcome the EGFR-TKI resistance.

Free Research Field

肺癌