PO.ET01.06 · 实验与分子治疗
HER2驱动的非小细胞肺癌在微小残留病阶段的TKI适应性耐药可通过细胞表面靶向疗法进行靶向
TKI adaptive resistance in HER2-driven non-small cell lung cancer at minimal residual disease stage can be targeted using cell surface-directed therapies
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：HER2突变驱动1-2%的非小细胞肺癌（NSCLC），近期的HER2靶向抗体药物偶联物和酪氨酸激酶抑制剂（TKI），如曲妥珠单抗-德鲁替康和zongertinib，已显著改善了结局。然而，这些方法仍无法治愈，几乎所有患者都会出现疾病进展。迫切需要能够清除微小残留病（MRD）的新型策略。由于缺乏细胞表面动态特征的表征，在HER2领域开发识别TKI适应后存在或上调的细胞膜蛋白的细胞表面靶向疗法仍处于欠发展状态。
方法：以不同剂量的zongertinib处理HER2突变型NSCLC细胞系以建立敏感性数值（CellTiter-Glo）。一株HER2突变、zongertinib不敏感的小细胞肺癌细胞系（H446）作为阴性对照。通过蛋白质印迹和流式细胞术在TKI初治和TKI耐受状态（IC50和IC90 zongertinib暴露）下定量检测肺癌中扩增的可靶向受体和标志物的总表达和细胞表面表达。随后以细胞表面靶向疗法处理HER2驱动（TKI敏感和耐药）细胞系和对照细胞系24小时，并评估其毒性。
结果：我们证明HER2突变型NSCLC细胞系在初治状态与zongertinib诱导的MRD状态之间表现出细胞表面蛋白表达的动态变化。TKI敏感和TKI耐药的HER2驱动细胞系对靶向表面蛋白的疗法表现出高敏感性，这与其表达水平相关。
结论：HER2驱动的NSCLC细胞系在接受TKI治疗时表现出细胞表面蛋白的动态变化。这些蛋白可被成功靶向以根除TKI治疗后的残留NSCLC，支持这一途径作为根除MRD和预防HER2突变型NSCLC复发的合理治疗策略。正在进行的研究将为推进以治愈为目的的早期临床试验提供依据。
查看英文原文 English abstract
Background: HER2 mutations drive 1-2% of non-small cell lung cancers (NSCLCs), and recent HER2-directed antibody-drug conjugates and tyrosine kinase inhibitors (TKIs) such as trastuzumab-deruxtecan and zongertinib have significantly improved outcomes. However, these approaches remain non-curative, and nearly all patients develop progressive disease. Novel strategies capable of eliminating minimal residual disease (MRD) are urgently needed. Generating cell-surface-directed therapies that recognize cell membrane proteins present or upregulated upon TKI adaptation remain underdeveloped in the HER2 space due to lack of cell surface dynamic characterization.
Methods: HER2-mutant NSCLC cell lines were treated with zongertinib at varying doses to establish sensitivity values (CellTiter-Glo). A HER2-mutant, zongertinib-insensitive small cell lung cancer line (H446) served as a negative control. Total and cell surface expression of targetable receptors and markers amplified in lung cancers were quantified by western blot and flow cytometry in both, TKI-naïve and TKI-tolerant states (IC50 and IC90 zongertinib exposure). HER2-driven (TKI sensitive and resistant) and control lines were then treated with cell-surface-directed therapies for 24 hours and evaluated for their toxicity.
Results: We demonstrate that HER2-mutant NSCLC cell lines retained demonstrated dynamic changes in cell surface protein expression in treatment-naïve versus zongertinib-induced MRD states. TKI-sensitive and TKI-resistant HER2-driven lines demonstrated high sensitivity to therapies targeting surface proteins, which correlated with their level of expression.
Conclusions: HER2-driven NSCLC cell lines present dynamic changes in cell surface proteins when undergoing TKI treatment. These proteins can be successfully targeted to eradicate residual NSCLC after TKI treatment, supporting this avenue as a rational therapeutic strategy for eradicating MRD and preventing relapse in HER2-mutant NSCLC. Ongoing studies will inform advancement toward early-phase clinical trials with curative intent.
利益披露 Disclosure
M. El Kharbili, None..
D. Wilkinson, None..
P. Fecci, None..
K. Concannon, None.