# Targeting MET Signalling Activated by CPNE3‐RACK1 Interaction Through VWFA Domain to Suppress Lung Cancer Progression

## TL;DR

This study identifies CPNE3 as a driver of lung cancer progression through MET signaling and suggests targeting this pathway could improve treatment.

## Contribution

The novel contribution is identifying CPNE3's role in activating MET signaling via RACK1 interaction and demonstrating MET inhibition as a potential therapy.

## Key findings

- CPNE3 is overexpressed in non-small cell lung cancer and promotes tumor growth and metastasis.
- CPNE3 activates MET signaling by interacting with RACK1 through the VWFA domain.
- MET inhibition and RACK1 knockdown suppress CPNE3-driven tumor progression in vitro and in vivo.

## Abstract

Despite advances in diagnosis and treatment, the prognosis of non‐small cell lung cancer (NSCLC) remains poor. Therefore, it is urgent to identify potential molecular targets. In this study, we investigated the function and internal mechanism of CPNE3 in the malignant biological behaviour via RACK1/c‐MET signalling in NSCLC, and explored the feasibility of the MET inhibitor in NSCLC treatment. The expression of CPNE3 in normal tissues and lung cancer tissues was compared using a public database. The function of CPNE3 was investigated using CCK‐8 assays, clonogenic assays, EdU assays, Transwell assays and cell cycle analysis. Western blotting was used to detect the protein expression. The interaction between CPNE3 and RACK1 was examined by immunofluorescence staining and co‐immunoprecipitation (co‐IP). The in vitro and in vivo functions of the MET inhibitor JNJ‐38877605 were investigated. CPNE3 is overexpressed in NSCLC and facilitates tumorigenesis and metastasis by interacting with RACK1 through the VWFA domain, which further induces the activation of MET signalling. Accordingly, this process could be suppressed by the MET inhibitor and RACK1 knockdown in vitro and in vivo. CPNE3 is highly expressed in NSCLC and can promote the proliferation and migration of tumour cells. CPNE3 could interact with RACK1 through the VWFA domain and activate MET signalling. These findings may provide new insights into the development of novel therapeutic strategies for NSCLC.