Identification of resistance mechanism to ALK-TKIs in leptomeningeal carcinomatosis (LMC) model with EML4-ALK NSCLC cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16738
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa University
• Principal Investigator: Arai Sachiko 金沢大学, がん進展制御研究所, 特任助手 (80824870)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 薬剤耐性 / ALK肺癌 / 中枢神経系転移

Outline of Final Research Achievements

This study aimed to clarify the mechanism of resistance to alectinib, a second-generation ALK-TKI, in Leptomeningeal carcinomatosis (LMC) and seek a novel therapeutic strategy. First, we induced alectinib resistance in an LMC mouse model using the ALK-rearranged NSCLC cell line A925L by continuous oral alectinib treatment, established AR cells from this model. AR cells acquired resistance through EGFR activation due to overexpression of its ligand, amphiregulin (AREG). In the LMC model with AR cells, combined treatment with alectinib and an EGFR-TKI successfully controlled LMC progression. Moreover, notably high AREG levels were detected in the cerebrospinal fluid from ALK-rearranged NSCLC patients with alectinib-resistant LMC compared with those in EGFR-mutated NSCLC patients with EGFR-TKI-resistant LMC or patients without LMC.
These findings indicate the potential of novel therapies dual-targeting ALK and EGFR against ALK-TKI-resistant LMC in ALK-rearranged NSCLC patients.

Free Research Field

薬剤耐性

Academic Significance and Societal Importance of the Research Achievements

髄膜癌腫症や脳転移などの中枢神経系（CNS）転移は肺癌の20～30％に発症し、患者のQOLを著しく低下させる危篤な病態であるが、CNS転移が耐性獲得による病勢増悪の場となることが多く、CNSにおける耐性の分子機構解明やCNSにも有効な分子標的薬の開発が特に注目されてきている。本研究では、ヒトALK肺癌細胞株をマウスの髄腔に移植したモデルにおいてアレクチニブ耐性を誘導し、得られた耐性株を用いて耐性機構を解明するため、in vitroの培養とは異なり患者と同様の生体内における薬物動態や血液脳関門を含む脳微小環境も反映した耐性機構の発見である。