PURPOSE Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. EXPERIMENTAL DESIGN We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. RESULTS ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. CONCLUSIONS These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

中文翻译：

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ONO-7475是一种新型AXL抑制剂，可抑制EGFR突变的非小细胞肺癌对初始EGFR-TKI治疗的适应性耐药性。

目的目前，尚无一种包括分子靶向药物的最佳治疗策略可用于治疗对奥西替尼具有耐药性的EGFR突变非小细胞肺癌（NSCLC）患者。因此，最初的治疗干预对于这些患者的延长生存期至关重要。已知无足动物（AXL）信号传导的激活与对EGFR酪氨酸激酶抑制剂（EGFR-TKIs）的内在和获得性耐药有关。在这项研究中，我们研究了使用新型AXL抑制剂ONO-7475对抗AXL诱导的对EGFR-TKIs耐受的最佳治疗策略。实验设计我们在体内和体外实验中研究了ONO-7475与EGFR-TKIs在EGFR突变的NSCLC细胞中的疗效。我们调查了对初始EGFR-TKIs获得性耐药的EGFR突变NSCLC患者的肿瘤中AXL表达与奥西替尼的临床结局之间的相关性。结果ONO-7475使过表达AXL的EGFR突变NSCLC细胞对EGFR-TKIs osimertinib和dacomitinib敏感。另外，ONO-7475抑制了EGFR-TKI耐受细胞的出现和维持。在用奥西替尼治疗的细胞系衍生的过表达AXL的EGFR突变的肺癌异种移植模型中，与单独使用奥西替尼或获得对奥西替尼耐药后的组合相比，ONO-7475和奥西替尼的初始联合治疗显着使肿瘤消退并延迟了肿瘤的再生长。EGFR-TKI难治性肿瘤中的AXL表达与奥西替尼的敏感性不相关。