Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer.
Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer.
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DOI：
10.18632/oncotarget.3380
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发表时间：
2015-04-30
期刊：
影响因子：
--
通讯作者：
Lee SK
中科院分区：
文献类型：
--
作者：
Bae SY;Hong JY;Lee HJ;Park HJ;Lee SK
对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）（如吉非替尼）的获得性耐药仍然是非小细胞肺癌（NSCLC）治疗中的一个主要问题。AXL激活增加已被确定为NSCLC治疗中EGFR-TKI获得性耐药的新机制。然而，不受控制的AXL表达的原因尚未完全了解。在这里，我们首先证明，AXL是过表达的收购吉非替尼耐药细胞系（H292-Gef）作为缓慢营业额的结果，AXL是早老素依赖性调节膜内蛋白水解（PS-RIP）降解。基于这些发现，我们试图通过用芫花定（Yuanhuadine，YD）（一种有效的NSCLC抗肿瘤药物）治疗吉非替尼耐药的NSCLC细胞来增强AXL的降解，以克服获得性吉非替尼耐药。用YD治疗有效地抑制癌细胞在体外和体内的存活。在机制上，YD加速了PS-RIP对AXL的周转，并导致全长AXL的下调。因此，通过降解过表达的AXL调节蛋白水解过程可能是治疗NSCLC和EGFR-TKI耐药NSCLC的有吸引力的治疗策略。
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, remains a major problem in non-small cell lung cancer (NSCLC) treatment. Increased activation of AXL has been identified as a novel mechanism for acquired resistance to EGFR-TKIs in NSCLC treatment. However, the cause of uncontrolled AXL expression is not fully understood. Here, we first demonstrate that AXL is overexpressed in an acquired gefitinib-resistant cell line (H292-Gef) as a result of slow turnover and that AXL is degraded by presenilin-dependent regulated intramembrane proteolysis (PS-RIP). Based on the findings, we attempted to enhance AXL degradation to overcome acquired gefitinib-resistance by the treatment of gefitinib-resistant NSCLC cells with yuanhuadine (YD), a potent antitumor agent in NSCLC. Treatment with YD effectively suppressed the cancer cell survival in vitro and in vivo. Mechanistically, YD accelerated the turnover of AXL by PS-RIP and resulted in the down-regulation of the full-length AXL. Therefore, the modulation of the proteolytic process through degradation of overexpressed AXL may be an attractive therapeutic strategy for the treatment of NSCLC and EGFR-TKI-resistant NSCLC.
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