PDF(Pubmed)
Abstract：
UNASSIGNED: EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC.
UNASSIGNED: We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab.
UNASSIGNED: Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab.
UNASSIGNED: Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.
UNASSIGNED: We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab.
UNASSIGNED: Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab.
UNASSIGNED: Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.
摘要：
■EGFR酪氨酸激酶抑制剂是EGFR突变晚期NSCLC患者的标准治疗药物。然而，一些患者在一线治疗中对EGFR酪氨酸激酶抑制剂表现出原发性耐药.AXL,TYRO3，AXL的成员，和受体酪氨酸激酶的MERTK家族，在EGFR突变的NSCLC中参与对EGFR酪氨酸激酶抑制剂的原发性耐药。
我们使用尸检样本和来自EGFR突变NSCLC患者的患者细胞系研究了空间肿瘤异质性，该患者对厄洛替尼加雷莫鲁单抗具有原发性耐药性。
■定量聚合酶链反应分析显示，AXLmRNA表达在每个转移部位有所不同。此外,AXL表达水平可能与厄洛替尼联合雷莫西单抗治疗的有效性呈负相关。对在治疗开始前从左胸腔积液建立的患者来源的细胞系的分析显示,与EGFR酪氨酸激酶抑制剂单一疗法或这些抑制剂与雷莫鲁单抗的组合疗法相比,EGFR酪氨酸激酶抑制剂和AXL抑制剂的组合显著抑制细胞活力并增加细胞凋亡。
■我们的观察表明，AXL表达可能在EGFR突变的NSCLC患者的空间肿瘤异质性和对EGFR酪氨酸激酶抑制剂的原发性耐药的进展中起关键作用。
我们使用尸检样本和来自EGFR突变NSCLC患者的患者细胞系研究了空间肿瘤异质性，该患者对厄洛替尼加雷莫鲁单抗具有原发性耐药性。
■定量聚合酶链反应分析显示，AXLmRNA表达在每个转移部位有所不同。此外,AXL表达水平可能与厄洛替尼联合雷莫西单抗治疗的有效性呈负相关。对在治疗开始前从左胸腔积液建立的患者来源的细胞系的分析显示,与EGFR酪氨酸激酶抑制剂单一疗法或这些抑制剂与雷莫鲁单抗的组合疗法相比,EGFR酪氨酸激酶抑制剂和AXL抑制剂的组合显著抑制细胞活力并增加细胞凋亡。
■我们的观察表明，AXL表达可能在EGFR突变的NSCLC患者的空间肿瘤异质性和对EGFR酪氨酸激酶抑制剂的原发性耐药的进展中起关键作用。
