Abstract：
Favorable clinical evidence suggests that the next trend in new treatments for advanced non-small cell lung cancer (NSCLC) will be combination therapies. However, inevitable epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance greatly limits the clinical efficacy of patients carrying EGFR-activating mutants. In this study, we found a patient with clinical osimertinib resistance who regained a positive response after osimertinib plus anlotinib treatment. Two osimertinib-resistant cell lines were constructed, and AXL conferred resistance to osimertinib in NSCLC cell lines. The combined effects of anlotinib and osimertinib restored sensitivity to osimertinib in two osimertinib-resistant NSCLC cell lines and in xenografts. Moreover, anlotinib inhibits the phosphorylation of AXL in both resistant cell lines. Mechanistically, we confirmed that MYC binds to the promoter of AXL to promote its transcription in NSCLC cells, and we demonstrated that anlotinib combined with osimertinib treatment enhances the anti-tumor effect by inactivating the c-MET/MYC/AXL axis to reverse osimertinib resistance in NSCLC. In conclusion, our results provide strong support that this combination therapy may be effective in enhancing the efficacy of treatments in patients with advanced NSCLC.
摘要：
有利的临床证据表明，晚期非小细胞肺癌（NSCLC）新疗法的下一个趋势将是联合疗法。然而,不可避免的表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）耐药极大地限制了携带EGFR激活突变体的患者的临床疗效。在这项研究中,我们发现一名临床奥希替尼耐药患者在奥希替尼联合安洛替尼治疗后恢复了阳性反应.构建了两种奥希替尼耐药细胞系，和AXL在NSCLC细胞系中赋予奥希替尼耐药性。在两种奥希替尼耐药的NSCLC细胞系和异种移植物中，安洛替尼和奥希替尼的联合作用恢复了对奥希替尼的敏感性。此外，安洛替尼抑制两种抗性细胞系中AXL的磷酸化。机械上,我们证实MYC与AXL的启动子结合以促进其在NSCLC细胞中的转录，我们证明,安洛替尼联合奥希替尼治疗可通过使c-MET/MYC/AXL轴失活来逆转NSCLC中的奥希替尼耐药,从而增强抗肿瘤作用.总之,我们的研究结果有力地支持了这种联合治疗可以有效提高晚期NSCLC患者的治疗效果.
