Abstract:
The amplification of MET is a major cause of acquired resistance to targeted therapy in EGFR-mutant non-small-cell lung cancer (NSCLC), only to be temporarily restrained by the partial efficacy of MET inhibitors. This study reveals that the MET inhibitor has unexpectedly limited efficacy due to amplified MET triggering a strong positive feedback loop in the Wnt/β-catenin signaling pathway, allowing optimal functionality even when the MET pathway is suppressed again. To test this conjecture and specifically target the Wnt/β-catenin pathway, a cleverly designed Wnt condensative pro drug called WntSI is developed using reversible supramolecular self-assembly driven by liquidliquid phase separation (LLPS). This process involves a MET/pH-responsive peptide (Tyr-Pep) and a potent Wnt inhibitor known as CA. Upon recognition and phosphorylation of Tyr-Pep by over expressed MET in cells, it disrupts LLPS propensity and facilitates the disintegration of WntSI. Consequently,this enables it to suppress the carcinogenic effect mediated by β-catenin,effectively overcoming acquired resistance to EGFR-TKIs caused by MET amplification in both cell line-derived and patient-derived tumor xenograft (PDX) mouse models while maintaining exceptional biosecurity. This effective strategy not only suppresses the Wnt/β-catenin signaling pathway selectively, but also serves as an innovative example for pro-drug development through biologically responsive LLPS.
摘要:
MET的扩增是EGFR突变型非小细胞肺癌(NSCLC)对靶向治疗的获得性耐药的主要原因。只能被MET抑制剂的部分疗效暂时抑制。这项研究表明,由于扩增的MET在Wnt/β-catenin信号通路中触发了强大的正反馈回路,因此MET抑制剂的功效出乎意料地有限。即使MET途径再次被抑制,也允许最佳功能。为了检验这一推测并特异性靶向Wnt/β-catenin通路,一种巧妙设计的Wnt缩合前药称为WntSI是使用液液相分离(LLPS)驱动的可逆超分子自组装开发的。该过程涉及MET/pH响应肽(Tyr-Pep)和称为CA的有效Wnt抑制剂。在细胞中过表达的MET识别和磷酸化Tyr-Pep时,它破坏了LLPS倾向,促进了WntSI的解体。因此,这使得它能够抑制β-连环蛋白介导的致癌作用,在细胞系来源和患者来源的肿瘤异种移植(PDX)小鼠模型中,有效克服了由MET扩增引起的对EGFR-TKIs的获得性耐药性,同时保持了出色的生物安全性。这种有效的策略不仅选择性地抑制了Wnt/β-catenin信号通路,但也是通过生物响应性LLPS开发前药的创新范例。