Sun Dantong, Hou Helei, Feng Feiyue, Wu Weizheng, Tan Jingyu, Xie Tongji, Liu Jiayu, Wang Jinsong, Qian Haili, Li Junling, Xing Puyuan
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Exp Hematol Oncol. 2025 Jan 7;14(1):3. doi: 10.1186/s40164-024-00594-4.
Osimertinib has emerged as a critical element in the treatment landscape following recent clinical trials. Further investigation into the mechanisms driving resistance to Osimertinib is necessary to address the restricted treatment options and survival advantages that are compromised by resistance in patients with EGFR-mutated lung adenocarcinoma (LUAD).
Spatial transcriptomic and proteomic analyses were utilized to investigate the mechanisms of Osimertinib resistance. Co-IP, MS, RNA-seq, ChIP-seq, RIP-seq, and ATAC-seq were performed in cell lines to further explore the mechanism. To validate the findings, in vitro and in vivo molecular experiments were conducted.
We found that the ARID1A deficiency results in resistance to Osimertinib by hindering programmed cell death through the EZH2/PTEN/E2F1 axis. This altered axis influences PD-L1 transcription through E2F1-mediated promoter activation and PD-L1 translation via the MDM2/eIF5B/PD-L1 axis. Subsequently, ARID1A deficiency results in increased expression of eIF5B and Importin-β1, promoting PD-L1 nuclear-translocation. The nuclear PD-L1 (nPD-L1) interacts with CD44, leading to nPD-L1 complex formation, activation of the RASGEF1A promoter, initiation of the Ras pathway, and contributing to Osimertinib resistance. Targeting the transcription, translation and nuclear-translocation of PD-L1 using lipid nanoparticles (LNPs) overcomes ARID1A deficiency-induced resistance.
ARID1A deficiency promotes PD-L1 nuclear translocation and induces Osimertinib resistance.
在最近的临床试验之后，奥希替尼已成为治疗领域的关键要素。进一步研究导致对奥希替尼耐药的机制，对于解决表皮生长因子受体（EGFR）突变的肺腺癌（LUAD）患者因耐药而受限的治疗选择和生存优势受损的问题是必要的。
利用空间转录组学和蛋白质组学分析来研究奥希替尼耐药的机制。在细胞系中进行免疫共沉淀（Co-IP）、质谱（MS）、RNA测序（RNA-seq）、染色质免疫沉淀测序（ChIP-seq）、RNA免疫沉淀测序（RIP-seq）和染色质转座酶可及性测序（ATAC-seq），以进一步探索该机制。为验证研究结果，进行了体外和体内分子实验。
我们发现，AT丰富交互结构域1A（ARID1A）缺陷通过EZH2/PTEN/ E2F1轴阻碍程序性细胞死亡，从而导致对奥希替尼耐药。这种改变的轴通过E2F1介导的启动子激活影响程序性死亡配体1（PD-L1）转录，并通过MDM2/真核翻译起始因子5B（eIF5B）/PD-L1轴影响PD-L1翻译。随后，ARID1A缺陷导致eIF5B和输入蛋白β1（Importin-β1）表达增加，促进PD-L1核转位。细胞核内的PD-L1（nPD-L1）与CD44相互作用，导致nPD-L1复合物形成、RAS鸟嘌呤核苷酸交换因子1A（RASGEF1A）启动子激活、Ras途径启动，并导致对奥希替尼耐药。使用脂质纳米颗粒（LNP）靶向PD-L1的转录、翻译和核转位可克服ARID1A缺陷诱导的耐药。
ARID1A缺陷促进PD-L1核转位并诱导对奥希替尼耐药。
