osimertinib resistance leptomeningeal carcinomatosis model of EGFR-mutant model

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17213
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kitasato University
• Principal Investigator: Otani Sakiko 北里大学, 医学部, 助教 (60439081)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: EGFR陽性肺癌 / 髄膜癌腫症 / オシメルチニブ耐性

Outline of Final Research Achievements

This study aimed to clarify the mechanism of resistance to osimertinib, a third-generation EGFR-TKI, in Leptomeningeal carcinomatosis (LMC) and seek a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) by continuous oral osimertinib treatment, established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the KRAS-G12V mutation in resistant cells. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.

Free Research Field

胸部腫瘍

Academic Significance and Societal Importance of the Research Achievements

オシメルチニブは、EGFR遺伝子変異陽性非小細胞肺癌患者対する標準治療薬であり、約70％の症例において奏効することが知られている。髄液移行性も高く中枢神経系(CNS)病変に対する有効性も高い一方、長期治療中に髄膜癌腫症や脳転移等のCNS転移が耐性獲得による病勢増悪の場となり患者のQOLを著しく低下させることが多い。本研究では、オシメルチニブ耐性LMC in vivo イメージングモデルから樹立したがん細胞株（GOR＃2）よりKRAS-G12V変異を検出し、in vivoにおいてオシメルチニブとMEK阻害薬との併用で耐性を克服できる可能性が示されたことに大きな意義があるものと考える。