IGF2BP3-调节受体酪氨酸激酶的联合抑制为癌症三阴性提供了一种新的治疗策略

摘要(中文译文)

背景：表皮生长因子受体（EGFR）在三阴性乳腺癌（TNBC）中具有高阳性率和强特异性，长期以来被认为是该亚型的特征之一。然而，EGFR抑制剂在TNBC治疗中的临床疗效有限。既往研究表明，TNBC中多种受体酪氨酸激酶（RTKs）被激活。这些RTKs通过二聚化协同激活下游通路磷酸化，导致EGFR单药治疗无效。这凸显了针对多种RTKs的联合策略治疗TNBC的必要性。方法：已发表的厄洛替尼耐药TNBC患者来源异种移植模型的bulk RNA测序数据集揭示了厄洛替尼耐药组织中基因集的变化。采用RNA免疫沉淀和甲基化RNA免疫沉淀测序检测胰岛素样生长因子2 mRNA结合蛋白3（IGF2BP3）共同调控的RTKs。通过RNA pull-down和分子对接阐明IGF2BP3与RTKs之间的相互作用位点。采用计算虚拟对接、层次筛选、微量热泳动和细胞毒性实验筛选旨在破坏IGF2BP3-RTK相互作用的小分子抑制剂。通过计算联合指数确定药物协同效应。结果：在本研究中，我们发现IGF2BP3能够以m6A依赖的方式协同调控多种RTKs的mRNA并激活RTKs表达，因此可能是解决耐药问题的关键点。在阐明IGF2BP3蛋白与RTK mRNA之间的相互作用位点后，我们鉴定出木犀草苷——一种能够破坏IGF2BP3-RTK相互作用的小分子抑制剂——作为酪氨酸激酶抑制剂（TKI）疗效的有前景的增强剂。此外，我们提出了一种将木犀草苷与TKI联合使用的新型治疗策略，并选择EGFR/MET双特异性抗体埃万妥单抗作为TNBC靶向治疗的最佳候选药物。结论：我们的研究提供了IGF2BP3介导EGFR抑制剂耐药的机制性见解，并提出了一种新兴的联合方法来克服TNBC的治疗局限性。

Abstract

BACKGROUND: Epidermal growth factor receptor (EGFR), characterized by its high positivity rate and strong specificity in triple-negative breast cancer (TNBC), has long been recognized as one of the characteristics of this subtype. However, EGFR inhibitors have demonstrated limited clinical efficacy in TNBC treatments. Previous studies revealed that multiple receptor tyrosine kinases (RTKs) were activated in TNBC. These RTKs cooperate through dimerization to activate downstream pathway phosphorylation, rendering EGFR monotherapy ineffective. This highlights the necessity for combinatorial strategies targeting multiple RTKs to treat TNBC. METHODS: Published bulk-RNA sequencing datasets from erlotinib resistant TNBC patient-derived xenografts model revealed changes in gene sets in erlotinib resistant tissues. RNA immunoprecipitation and methylated RNA immunoprecipitation sequencing were used to detect co-regulated RTKs by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). RNA pull-down and molecular docking clarified the interaction sites between IGF2BP3 and RTKs. Computational virtual docking, hierarchical screening, microscale thermophoresis and cytotoxicity assays were employed to screen small-molecule inhibitors aimed at disrupting IGF2BP3-RTK interactions. The determination of drug synergistic effects was achieved through the calculation of the combination index. RESULTS: In this study, we identified IGF2BP3 could coordinately regulate multiple RTKs’ mRNA through an m6A-dependent manner and activate RTKs expression, and thus could be the key point to address the drug resistance problem. After clarifying the interaction sites between IGF2BP3 protein and RTK mRNAs, we identified cynaroside, a small-molecule inhibitor capable of disrupting IGF2BP3-RTK interactions, as a promising enhancer of tyrosine kinase inhibitor (TKI) efficacy. Moreover, we proposed a novel therapeutic strategy by combining cynaroside with TKI and chose the EGFR/MET bispecific antibody amivantamab for the best candidate in TNBC target treatment. CONCLUSIONS: Our study provide a mechanistic insight into IGF2BP3-mediated EGFR inhibitor resistance and present an emerging combinatorial approach to overcome therapeutic limitations in TNBC.

如何引用

Journal of experimental & clinical cancer research : CR 的其他文献

• 翻译景观的无偏分析揭示了TNFR2在结直肠癌癌症中是翻译依赖性的脆弱性