Novel strategy targeting apoptosis regulators for non-small cell lung cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K17200
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Nippon Medical School
• Principal Investigator: Nakamichi Shinji 日本医科大学, 医学部, 助教 (10837446)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 肺癌 / 薬剤耐性 / 薬物療法 / 分子標的薬

Outline of Final Research Achievements

Molecular targeted therapy has shown dramatic efficacy in the treatment of lung cancer. However, drug resistance is a critical problem, and the prognosis of lung cancer remains poor. This study aimed to analyze the resistant mechanism of advanced non-small cell lung cancer (NSCLC) from the point of apoptosis and to develop a novel therapeutic strategy. Using EGFR mutation-positive NSCLC cells, we generated osimertinib-resistant cells. We confirmed that the expression of phosphorylated ERK was significantly upregulated in all resistant cells and associated with resistance to apoptosis through BIM. The efficacy of carnosic acid, ERK inhibitor, and proteasome inhibitor on resistant cells was confirmed. Our data suggested that FOXO3a is associated with apoptosis resistance, and these drugs may be promising new therapies.

Free Research Field

肺癌、薬剤耐性、抗悪性腫瘍薬、薬物療法

Academic Significance and Societal Importance of the Research Achievements

進行肺癌の薬物治療において分子標的治療は劇的な効果を示すが、その薬剤獲得耐性が問題であり、以前として予後は厳しいままである。本研究は、アポトーシスに着目したこれまでの治療と異なる新しい視点から、肺癌において分子標的薬剤の獲得耐性の分子病態メカニズムを解明し、薬剤耐性を克服する新規薬物療法戦略をを提案した点において学術的意義や社会的意義は高いと考えられる。