Qu Tianyu, Song Lei, Xu Jiali, Lu Xiyi, Yin Dandan, Dai Jiali, Zhang Chen, Guo Renhua, Zhang Erbao
Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China.
Cancer Res. 2025 Aug 15;85(16):3052-3071. doi: 10.1158/0008-5472.CAN-23-3748.
Acquired resistance to EGFR tyrosine kinase inhibitors (TKI) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA MYLK-AS1 supporting acquired TKI resistance in lung cancer. Elevated expression of MYLK-AS1 correlated with TKI resistance in samples from patients with NSCLC and cell lines. c-Myc mediated transcriptional activation of MYLK-AS1, and m6A modification promoted posttranscriptional upregulation. Mechanistically, MYLK-AS1 bound and directly drove phase separation of interleukin enhancer-binding factor 3 (ILF3), thus interacting with the 3' untranslated region of glutamate dehydrogenase 1 (GLUD1) to posttranscriptionally promote its mRNA stability. MYLK-AS1-mediated GLUD1 upregulation accelerated mitochondrial glutamine catabolism, promoting TKI resistance. Inhibition of GLUD1 with the small-molecule inhibitor R162 in TKI-resistant models suppressed cell proliferation in vitro and tumor growth in vivo. Moreover, knockdown of MYLK-AS1 also enhanced drug sensitivity in TKI-resistant patient-derived xenograft models, suggesting its therapeutic potential. Collectively, these findings offer insights into the regulation of TKI resistance from the perspective of phase separation and metabolism and highlight targeting the MYLK-AS1/ILF3/GLUD1 axis as a potential strategy for improving the efficacy of EGFR TKIs in NSCLC.
MYLK-AS1 promotes resistance to EGFR inhibitors by inducing phase separation of ILF3 to stabilize GLUD1 and stimulate glutamine metabolism, highlighting this axis as a putative therapeutic target for overcoming resistance.
获得性表皮生长因子受体酪氨酸激酶抑制剂（TKI）耐药限制了分子靶向治疗在非小细胞肺癌（NSCLC）中的疗效。代谢重编程是肺癌的一个标志，可能导致TKI耐药。通过系统筛选和验证，我们确定了长链非编码RNA MYLK-AS1在肺癌获得性TKI耐药中发挥的作用。MYLK-AS1表达升高与NSCLC患者样本和细胞系中的TKI耐药相关。c-Myc介导MYLK-AS1的转录激活，且m6A修饰促进转录后上调。机制上，MYLK-AS1结合并直接驱动白细胞介素增强子结合因子3（ILF3）的相分离，从而与谷氨酸脱氢酶1（GLUD1）的3'非翻译区相互作用，转录后促进其mRNA稳定性。MYLK-AS1介导的GLUD1上调加速线粒体谷氨酰胺分解代谢，促进TKI耐药。在TKI耐药模型中用小分子抑制剂R162抑制GLUD1可抑制体外细胞增殖和体内肿瘤生长。此外，敲低MYLK-AS1也增强了TKI耐药的患者来源异种移植模型中的药物敏感性，表明其治疗潜力。总之，这些发现从相分离和代谢的角度为TKI耐药的调控提供了见解，并强调靶向MYLK-AS1/ILF3/GLUD1轴作为提高EGFR TKIs在NSCLC中疗效的潜在策略。
MYLK-AS1通过诱导ILF3相分离以稳定GLUD1并刺激谷氨酰胺代谢来促进对EGFR抑制剂的耐药，突出该轴作为克服耐药的假定治疗靶点。
