获得性抗性是肺癌中有效的分子靶向治疗的瓶颈。代谢适应是人类肺癌的独特标志之一，可能导致获得性抗性。在本研究中，我们发现通过IGF2BP3依赖的表观遗传修饰和代谢重编程之间的交叉对话，通过IGF2BP3-COX6B2轴介导的EGFR酪氨酸激酶抑制剂（TKIs）获得性耐药的一种新机制。TKI耐药的非小细胞肺癌患者中IGF2BP3上调，并且高IGF2BP3表达与减少总体生存率相关。肺癌细胞中RNA结合蛋白IGF2BP3的上调表达降低了对TKI治疗的敏感性，并通过促进氧化磷酸化（OXPHOS）加剧了药物抵抗的发展。 COX6B2 mRNA结合了IGF2BP3，并且对通过IGF2BP3介导的获得性EGFR-TKI抗性所需的氧化磷酸化（OXPHOS）有所增加。机械上，IGF2BP3以m6A依赖的方式结合COX6B2的3'未翻译区域，以增加COX6B2 mRNA的稳定性。此外，IGF2BP3-COX6B2轴调节烟酰胺代谢，可改变氧化磷酸化并促进EGFR-TKI获得性抗性。使用小分子抑制剂IACS-010759抑制OXPHOS可在体外和体内的gefitinib耐药患者衍生的异种移植模型中导致强烈的生长抑制。总的来说，这些发现表明IGF2BP3-COX6B2轴通过代谢重编程在TKI抗性中发挥关键作用，并赋予可靶向的代谢易感性，以克服肺癌对EGFR-TKI的获得性抗性。

Acquired resistance represents a bottleneck for effective molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer that might contribute to acquired resistance. In this study, we discovered a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by IGF2BP3-dependent crosstalk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis. IGF2BP3 was upregulated in TKI-resistant non-small cell lung cancer patients, and high IGF2BP3 expression correlated with reduced overall survival. Upregulated expression of the RNA binding protein IGF2BP3 in lung cancer cells reduced sensitivity to TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was required for increased OXPHOS and acquired EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 bound to the 3'-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, the IGF2BP3-COX6B2 axis regulated nicotinamide metabolism, which can alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer.