吉非替尼
癌症研究
抗药性
泛素
肺癌
化学
酪氨酸激酶
癌症
蛋白质降解
蛋白酶体
激酶
药品
细胞
酪氨酸
癌细胞
磷酸化
信号转导
表皮生长因子受体抑制剂
降级(电信)
药理学
下调和上调
细胞生物学
细胞培养
突变
酪氨酸激酶抑制剂
后天抵抗
受体酪氨酸激酶
细胞生长
药物发现
机制(生物学)
作者
Dan Liu,Minxia Liu,Dongjin Lv,Yuxiang Li,Hongjuan Guo,Bingxiao Lu,Hao Leng,Ruyu Yan,Hongtao Yu,Tomas Blom,Kecheng Zhou
摘要
Tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC); however, acquired resistance remains a major clinical challenge. While lysosomes have been implicated in drug resistance, their precise role in EGFR-TKI resistance remains unclear. In this study, we found that EGFR-TKI, including gefitinib and osimertinib, impaired WWP2-mediated proteasomal degradation of LAPTM4B. Through analysis of clinical tumor samples, genetic manipulation, and functional assays, we identify the lysosomal protein LAPTM4B as a key driver of EGFR-TKI resistance by enhancing EGFR phosphorylation and downstream signaling. Mechanistically, LAPTM4B interacts with ATP1A1 and facilitates its endocytosis, while simultaneously preventing its degradation by suppressing TRIM8-mediated K63-linked ubiquitination and proteasomal turnover. This stabilization of ATP1A1 enhances lysosomal acidification, ultimately promoting EGFR-TKI resistance. To identify potential therapeutic strategies, we conducted an unbiased high-content drug screen and identified compounds that suppress LAPTM4B expression. These compounds synergistically enhance the efficacy of EGFR-TKIs in NSCLC models in vitro and in vivo, with minimal toxicity. Integrative analyses of patient tissue samples, cellular models, an animal model, and cancer databases highlight the critical role of the LAPTM4B-ATP1A1-lysosomal acidification axis in EGFR-TKI resistance, providing a promising therapeutic avenue for overcoming resistance in EGFR-mutant NSCLC.
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