Reversing MET‐Mediated Resistance in Oncogene‐Driven NSCLC by MET‐Activated Wnt Condensative Prodrug

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.