IL-26 mediates epidermal growth factor receptor-tyrosine kinase inhibitor resistance in triple-negative breast cancer cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16389
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Juntendo University
• Principal Investigator: Itoh Takumi 順天堂大学, 大学院医学研究科, 特任助教 (80811835)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 炎症性サイトカイン / IL-26 / 乳癌 / 薬剤耐性

Outline of Final Research Achievements

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other breast cancer subtypes. Although epidermal growth factor receptor (EGFR) is overexpressed in TNBC, clinical trials with EGFR inhibitors including tyrosine kinase inhibitors (EGFR-TKI) in TNBC have heretofore been unsuccessful. In this study, to understand the molecular mechanisms involved in the differences in EGFR-TKI efficacy on TNBC between human and mouse, we focused on the effect of IL-26, which is absent in mice. We investigated the mechanisms involved in IL-26-mediated EGFR-TKI resistance in TNBC. IL-26 induced activation of AKT and JNK signaling against EGFR-TKI-induced endoplasmic reticulum (ER) stress, leading to tumor growth. Meanwhile, the blockade of IL-26 overcame EGFR-TKI resistance in TNBC. Our work provides novel insights into the mechanisms of EGFR-TKI resistance in TNBC, while also suggesting IL-26 as a possible therapeutic target in TNBC.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究では、申請者が培ってきた独自の疾患モデルや技術を使用してEGFR-TKI耐性におけるIL-26の役割を明らかにし、IL-26による薬剤耐性メカニズムを解明した。さらに、ヒト化抗IL-26mAbの中和活性評価を行い、マウスのTNBCモデルに対するIL-26をターゲットとした治療法の有効性を確認した。これにより、IL-26抗体はEGFR-TKI耐性獲得が問題となっている肺癌や治療標的の無い難治性癌などに対しても、新しい治療法を確立するシーズとなる可能性が期待できる。さらに、樹立した抗体は、IL-26が関与する炎症性疾患の治療応用にも将来的に波及させることも可能だと考える。