Deng Qin-Fang, Li Chao, Liu Jing, Ji Xian-Xiu, Wan Xiao-Ying, Wang Chun-Yan, Sun Hui, Fang Qi-Yu, Gu Wei-Qin, Ma Chao, Wang Hui-Yong, Zhou Cai-Cun, Li Yi-Xue, Xie Bo-Xiong, Zhou Song-Wen
Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
Smartquerier Gene Technology (Shanghai) Co., Ltd. Shanghai, China.
Am J Cancer Res. 2023 Aug 15;13(8):3517-3530. eCollection 2023.
Patients with non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) inevitably exhibit drug resistance, which diminishes therapeutic effects. Nonetheless, the molecular mechanisms of TKI resistance in NSCLC remain obscure. In this study, data from clinical and TCGA databases revealed an increase in DNMT3A expression, which was correlated with a poor prognosis. Using NSCLC organoid models, we observed that high DNMT3A levels reduced TKI susceptibility of NSCLC cells via upregulating inhibitor of apoptosis proteins (IAPs). Simultaneously, the DNMT3A subset, which escaped apoptosis, underwent an early senescent-like state in a CDKN1A-dependent manner. Furthermore, the cellular senescence induced by TKIs was observed to be reversible, whereas DNMT3A cells reacquired their proliferative characteristics in the absence of TKIs, resulting in subsequent tumour recurrence and growth. Notably, the blockade of DNMT3A/IAPs signals enhanced the efficacy of TKIs in DNMT3A tumour-bearing mice, which represented a promising strategy for the effective treatment of NSCLC.
接受酪氨酸激酶抑制剂（TKIs）治疗的非小细胞肺癌（NSCLC）患者不可避免地会出现耐药性，这会降低治疗效果。尽管如此，NSCLC中TKI耐药的分子机制仍不清楚。在本研究中，临床和TCGA数据库的数据显示DNMT3A表达增加，这与预后不良相关。使用NSCLC类器官模型，我们观察到高DNMT3A水平通过上调凋亡抑制蛋白（IAPs）降低了NSCLC细胞对TKI的敏感性。同时，逃避凋亡的DNMT3A亚群以CDKN1A依赖的方式进入早期衰老样状态。此外，观察到TKI诱导的细胞衰老具有可逆性，而DNMT3A细胞在没有TKI的情况下重新获得增殖特性，导致随后的肿瘤复发和生长。值得注意的是，阻断DNMT3A/IAPs信号增强了TKI对携带DNMT3A肿瘤小鼠的疗效，这代表了一种有效治疗NSCLC的有前景的策略。
