Development of metabolic-targeting therapy for overcoming resistance to EGFR-TKIs in non-small cell lung cancer cells

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K06893
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Shizuoka Cancer Center Research Institute
• Principal Investigator: Serizawa Masakuni 静岡県立静岡がんセンター(研究所), その他部局等, 主任研究員 (00569915)
• Co-Investigator(Kenkyū-buntansha): 楠原 正俊 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (40169991) ; 高橋 利明 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (50507415) ; 解良 恭一 群馬大学, 医学部, その他 (40400783)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: がん代謝標的療法 / 肺腺癌 / EGFR-TKI / 耐性 / オシメルチニブ / メタボローム解析

Outline of Final Research Achievements

This study aimed to identify the metabolic profile relevant to EGFR-TKI-resistance and develop targeted therapies for the altered metabolic signature. Especially, we focused on the development of metabolic-targeting therapy for overcoming resistance to the third-generation EGFR-TKI, osimertinib.
We established osimertinib-resistant cell line (EOSR) by using HCC827 lung adenocarcinoma cell line harboring the EGFR-activating mutation. As a result of metabolic profiling with capillary electrophoresis time of-flight mass spectrometry, EOSR cell line showed higher concentration of fructose 1,6-diphosphate and lactic acid compared to HCC827 cells, suggesting metabolic signatures indicative of enhanced glycolysis. Significant gains in the expression of only one gene of the hexokinase family was also detected in EOSR cells. A combination of a competitive glycolytic inhibitor, 2-deoxy-D-glucose, and osimertinib restored osimertinib sensitivity in the EOSR cells showing glycolysis dependence.

Free Research Field

Molecular oncology