Development of therapy for overcoming resistance to mutant selective EGFR-TKI due to persistance of apoptosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K09649
• 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: Kanazawa University
• Principal Investigator: TAKEUCHI SHINJI 金沢大学, 附属病院, 講師 (90565384)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: EGFR変異 / 非小細胞肺癌 / アポトーシス / Osimertinib / HDAC阻害薬

Outline of Final Research Achievements

The BIM deletion polymorphism is associated with apoptosis resistance to EGFR-TKIs, such as gefitinib, in NSCLC harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a mutant selective EGFR-TKI.
EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib and this resistance was overcome by combined use with vorinostat in vitro and in vivo. Experiments with homozygous BIM deletion-positive EGFR-mutated NSCLC cells revealed that vorinostat increased the expression of active BIM protein and induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism.

Free Research Field

呼吸器悪性腫瘍の分子標的治療

Academic Significance and Societal Importance of the Research Achievements

BIM遺伝子多型は少量の血液で解析が可能で、患者への侵襲が少なく、簡便かつ正確に解析することができるため、薬剤耐性のバイオマーカーとして非常に有望である。本研究により、EGFR変異肺癌の標準治療であるOsimertinibの耐性にもBIM遺伝子多型が影響しており、HDAC阻害薬であるVorinostat併用治療が有効であることが示唆された。今後、BIM遺伝子多型をバイオマーカーとしたHDAC阻害薬併用治療の臨床開発が進むことが期待される。