This study investigated the role of anlotinib in restoring osimertinib sensitivity in EGFR-mutant non-small cell lung cancer (NSCLC) by targeting the Wnt/β-catenin/YAP signaling and PD-L1 expression. Using osimertinib-resistant HCC827 cells with high PD-L1 expression, a stable PD-L1 knockdown line (Sh-PD-L1) was generated through lentiviral vectors. Resistance was induced by stepwise exposure to osimertinib, and the two constructed resistant cell lines were named OR (osimertinib-resistant) and Sh-PD-L1-OR (PD-L1 knockdown osimertinib-resistant) cell lines. Functional assays, including wound healing, Transwell, and MTT, along with Western blot analysis, were conducted in both cell and animal models. Sh-PD-L1 significantly reduced PD-L1 and EGFR expression (P P P P P P P < 0.01), with decreased expression of EGFR, PD-L1, YAP, and β-catenin. These findings suggest that high PD-L1 expression promotes osimertinib resistance through activation of YAP and Wnt/β-catenin, and that anlotinib combined with osimertinib can reverse resistance by restoring GSK3β activity, activating the Hippo pathway, and inhibiting β-catenin signaling.
X Jing (Thu,) studied this question.