Rationale: Brain metastasis in patients with lung cancer is life-threatening. However, the molecular mechanism for this catastrophic disease remains elusive, and few druggable targets are available. Therefore, this study aimed to identify and characterize proteins that could be used as therapeutic targets./nMethods: Proteomic analyses were conducted to identify differentially expressed membrane proteins between brain metastatic lung cancer cells and primary lung cancer cells. A neuronal growth-associated protein, brain acid soluble protein 1 (BASP1), was chosen for further investigation. The clinical relevance of BASP1 in lung adenocarcinoma was first assessed. Tyrosine kinase activity assays and in vitro and in vivo functional assays were conducted to explore the oncogenic mechanisms of BASP1./nResults: The protein levels of BASP1 were positively associated with tumor progression and poor prognosis in patients with lung adenocarcinoma. Membrane-bound BASP1 increased EGFR signaling and stabilized EGFR proteins by facilitating their escape from the ubiquitin-proteasome pathway. Reciprocally, activation of EGFR recruited more BASP1 to the plasma membrane, generating a positive feedback loop between BASP1 and EGFR. Moreover, the synergistic therapeutic effects of EGFR tyrosine kinase inhibitor and arsenic trioxide led to a reduction in the level of BASP1 protein observed in lung cancer cells with acquired resistance to EGFR inhibitors./nConclusions: The reciprocal interaction between BASP1 and EGFR facilitates EGFR signaling in brain metastatic lung cancer. Targeting the newly identified BASP1-EGFR interaction could open new venues for lung cancer treatment.

中文翻译：

---

在BASP1和EGFR之间靶向阳性反馈作为肺癌进展的治疗策略

理由：肺癌患者的脑转移威胁生命。但是，这种灾难性疾病的分子机制仍然难以捉摸，几乎没有药物可治疗的靶标。因此，本研究旨在鉴定和表征可用作治疗靶标的蛋白质。/n方法：进行了蛋白质组学分析，以鉴定脑转移性肺癌细胞与原发性肺癌细胞之间差异表达的膜蛋白。神经元生长相关蛋白，脑酸可溶性蛋白1（BASP1），被选择用于进一步研究。首先评估了BASP1在肺腺癌中的临床相关性。酪氨酸激酶活性测定以及体内和体外功能测定进行了探索BASP1./n的致癌机制结果： BASP1的蛋白水平与肿瘤进展和预后不良的患者肺腺癌呈正相关。膜结合的BASP1通过促进其从遍在蛋白-蛋白酶体途径中逸出而增加了EGFR信号传导并稳定了EGFR蛋白。相反，EGFR的激活将更多的BASP1募集到质膜上，从而在BASP1和EGFR之间产生一个正反馈环。此外，EGFR酪氨酸激酶抑制剂和三氧化二砷的协同治疗作用导致在对EGFR抑制剂获得性耐药的肺癌细胞中观察到BASP1蛋白水平降低。/n结论：BASP1和EGFR之间的相互相互作用促进脑转移性肺癌中的EGFR信号传导。针对新近确定的BASP1-EGFR相互作用，可以为肺癌治疗开辟新的场所。