Overcoming EGFR-TKI resistance induced by the acquisition of cancer stem cell phenotype

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15963
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hyogo Medical University
• Principal Investigator: Kanemura Shingo 兵庫医科大学, 医学部, 非常勤講師 (20815245)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: EGFR遺伝子変異陽性肺癌 / EGFRチロシンキナーゼ阻害薬 / β3インテグリン / YAP/TAZ / 癌幹細胞化

Outline of Final Research Achievements

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) bring about high response rate and survival benefit to patients with EGFR mutation-positive non-small cell lung cancer. However, they eventually develop acquired resistance and tumor regrows.
In the present study, we found that stimulation by EGFR-TKIs enhanced the expression of intergrin β3 (ITGB3) in EGFR mutation-positive lung cancer cells, which promoted nuclear translocation of YAP/TAZ thorough activation of YES. YAP/TAZ work as transcriptional co-activators and induce expression of target genes associated with cell cycle progression and anti-apoptosis. Therefore, we considered that lung cancer cells acquire resistance to EGFR-TKI through ITGB3-mediated YAP/TAZ activation. Collectively, ITGB3-YAP/TAZ signal is regarded as a novel therapeutic candidate to overcome EGFR-TKI resistance in patients with EGFR mutation-positive lung cancer.

Free Research Field

胸部悪性腫瘍

Academic Significance and Societal Importance of the Research Achievements

EGFR-TKIがEGFR遺伝子変異陽性肺癌症例に対し極めて有効で、生存期間の改善に貢献している事は数々のevidenceから明らかであるが、耐性化が必発である。耐性機序の解明についての研究も盛んに行われ、T790Mといったgate keeper遺伝子変異による機序、Metの増幅などによる代替シグナルの活性化、小細胞肺癌化など複数の機序が明らかとなっているが、依然として20%以上の耐性機序は未解明のままである。今回の実験で、YAP/TAZがEGFR-TKIの耐性機序に関わっている事が示された事は、EGFR-TKI耐性機序の克服のための新たな知見として重要であると考える。