Overcoming ARID1A mutation-induced osimertinib resistance in EGFR-mutant NSCLC leptomeningeal carcinomatosis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07172
• 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: Kanazawa University
• Principal Investigator: Fukuda Koji 金沢大学, がん進展制御研究所, 助教 (10722548)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肺がん / EGFR / ARID1A / Osimertinib / WEE1 / 髄膜癌腫症 / CNS

Outline of Final Research Achievements

Osimertinib is an effective treatment for EGFR-mutant lung cancer and is also effective against central nervous system (CNS) metastases. However, resistance typically develops within 1-2 years, leading to poor prognosis, especially in leptomeningeal carcinomatosis (LMC). To elucidate the mechanisms of Osimertinib resistance and explore new therapeutic strategies, we established Osimertinib-resistant cell lines using a mouse model. Next-generation sequencing identified ARID1A mutations in the resistant cells. CRISPR-Cas9 screening revealed that WEE1 inhibition strongly induced apoptosis in these resistant cells. These findings suggest that ARID1A mutations contribute to resistance and that WEE1 is a promising therapeutic target.

Free Research Field

分子腫瘍学、腫瘍内科

Academic Significance and Societal Importance of the Research Achievements

OsimertinibはEGFR変異肺癌に対する有効な治療法ですが、1～2年で耐性を獲得し、特に髄膜癌腫症（LMC）の予後が不良です。我々の研究では、耐性の原因としてARID1A変異を同定し、CRISPR-Cas9スクリーニングを通じてWEE1阻害が耐性株のアポトーシスを誘導することを発見しました。この成果は、特に脳転移を起こした肺がん患者の治療法の開発に向けた新たな道を開き、予後改善に貢献する可能性があります。