Study to circumvent targeted drug resistance in leptomeningeal carcinomatosis of lung cancer

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05308
• 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: Kanazawa University
• Principal Investigator: Yano Seiji 金沢大学, がん進展制御研究所, 教授 (30294672)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 分子標的薬耐性 / 髄膜がん腫症 / EGFR-TKI

Outline of Final Research Achievements

In the leptomeningeal carcinomatosis (LMC) model of EGFR mutated lung cancer, we demonstrated that MET copy number gain caused resistance to 1st generation EGFR-tyrosine kinase inhibitors (TKI) and that combined use of MET inhibitor overcame the resistance. We also discovered 2 mutations which caused resistance to 3rd generation EGFR-TKI, osimertinib, in the LMC model. In the LMC model of ALK-rearranged lung cancer, we found that amphiregulin, an EGFR ligand, induced resistance to ALK-TKI alectinib and that combined use of EGFR-TKI overcame the resistance. In the brain metastasis model of NTRK1-rearranged cancer, we showed that NTRK1-G667C mutation caused resistance to TRK-A inhibitor entrectinib and that foretinib circumvent the resistance.

Free Research Field

臨床腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究において、肺がんの髄膜がん腫症における分子標的薬耐性の新たなメカニズムが同定されるとともに治療法の候補が見つかったことから、近い将来耐性克服を目指す臨床試験が行われ成果が患者に還元される可能性が生まれた。