Frizzled‐7‐targeting antibody (SHH002‐hu1) potently suppresses non–small‐cell lung cancer via Wnt/β‐catenin signaling

Abstract

Abstract Non–small‐cell lung cancer (NSCLC) is one of the deadliest cancers worldwide, and metastasis is considered one of the leading causes of treatment failure in NSCLC. Wnt/β‐catenin signaling is crucially involved in epithelial–mesenchymal transition (EMT), a crucial factor in promoting metastasis, and also contributes to resistance developed by NSCLC to targeted agents. Frizzled‐7 (Fzd7), a critical receptor of Wnt/β‐catenin signaling, is aberrantly expressed in NSCLC and has been confirmed to be positively correlated with poor clinical outcomes. SHH002‐hu1, a humanized antibody targeting Fzd7, was previously successfully generated by our group. Here, we studied the anti‐tumor effects of SHH002‐hu1 against NSCLC and revealed the underlying mechanism. First, immunofluorescence (IF) and near‐infrared (NIR) imaging assays showed that SHH002‐hu1 specifically binds Fzd7 + NSCLC cells and targets NSCLC tissues. Wound healing and transwell invasion assays indicated that SHH002‐hu1 significantly inhibits the migration and invasion of NSCLC cells. Subsequently, TOP‐FLASH/FOP‐FLASH luciferase reporter, IF, and western blot assays validated that SHH002‐hu1 effectively suppresses the activation of Wnt/β‐catenin signaling, and further attenuates the EMT of NSCLC cells. Finally, the subcutaneous xenotransplanted tumor model of A549/H1975, as well as the popliteal lymph node (LN) metastasis model, was established, and SHH002‐hu1 was demonstrated to inhibit the growth of NSCLC xenografts and suppress LN metastasis of NSCLC. Above all, SHH002‐hu1 with selectivity toward Fzd7 + NSCLC and the potential of inhibiting invasion and metastasis of NSCLC via disrupting Wnt/β‐catenin signaling, is indicated as a good candidate for the targeted therapy of NSCLC.