Development of a novel targeted therapy for EGFR mutation-positive lung cancer focusing on the Hippo pathway molecule MOB1

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07220
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kyushu University
• Principal Investigator: Tanaka Kentaro 九州大学, 医学研究院, 准教授 (00536849)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: YAP / Hippo pathway / EGFR / Apoptosis / NSCLC / MOB1

Outline of Final Research Achievements

The functional association between EGFR mutations in lung cancer and YAP, a transcriptional coactivator, which is a downstream of MOB1 that regulates cell growth and survival, was investigated. Under conditions of serum deprivation, EGF stimulation induced YAP activation in EGFR mutation-positive non-small cell lung cancer cell lines, but not in EGFR wild-type cell lines; even when EGFR was forced to express the mutant EGFR cell lines, EGF stimulation induced YAP activation only in mutant EGFR cells.
Furthermore, EGF stimulation under serum deprivation significantly induced apoptosis in wild-type cells, whereas Mutant-expressing cells were resistant to apoptosis; knockdown of YAP resulted in the observation of apoptosis in mutant-expressing cells as well.

Free Research Field

癌生物学

Academic Significance and Societal Importance of the Research Achievements

EGFR遺伝子変異陽性非小細胞肺癌においては、Hippo-MOB1下流の転写共役因子であるYAPがEGF刺激により活性化され、EGF誘導性アポトーシスに対する抵抗性を有することで細胞の生存に特異的に寄与することが明らかとなった。普遍的な増殖因子の一つであるEGFに対して、EGFR野生型細胞ではアポトーシスを介した増殖の制御が有効に機能する一方、EGFR変異陽性細胞においてはそのような制御が機能せず寧ろ異常な増殖を来し、発癌や癌の増大の一因となりうると考えられる。今後同経路及びクロストークすると考えられるRAS-MAPKキナーゼ経路の解析を継続し、Hippo経路を標的とした治療薬開発を進める。