A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer.

Yangbing Jin,Chenghong Peng,Xiaxing Deng,Baiyong Shen,Zehui Zhang,Hao Chen,Fanlu Li,Qian Zhan,Siyi Zou,Chenlei Wen

doi:10.3389/fonc.2021.634881

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the United States and has a 5-year survival rate of <4%. Although much effort has been invested in the research and development of pancreatic cancer drugs over the past 30 years, due to the lack of effective targetable carcinogenic drivers, no new targeted therapies that can improve patient prognosis have been approved for clinical use. SHR-A1403 is a new c-mesenchymal-epithelial transition factor (c-MET) antibody-drug conjugate that can be used for the targeted treatment of PDAC with high c-MET expression. This study reports for the first time the application prospects of SHR-A1403 in preclinical models of PDAC. SHR-A1403 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells and induced cell cycle arrest and apoptosis. These changes were caused by inhibition of intracellular cholesterol biosynthesis by SHR-A1403. Therefore, targeting c-MET through SHR-A1403 showed strong preclinical anti-tumour efficacy in pancreatic cancer. Our work suggests the potential application of c-MET-targeted antibody-drug conjugate treatment for PDAC in clinical practise.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the United States and has a 5-year survival rate of
SHR-A1403 (ADC), SHR-A1403 monoclonal antibody (mAb), and the free toxin SHR152852 were provided by Shanghai Hengrui Pharmaceutical Co., Ltd., China. c-mesenchymal-epithelial transition factor (c-MET), HMGCR, LSS, DHCR24, goat anti-rabbit IgG, and goat anti-mouse IgG antibodies were purchased from Abcam, and GAPDH (2118L), SNAIL (3879S), and βcatenin (8480P) antibodies were purchased from Cell Signalling Technology
To explore the MET expression pattern in PDAC and its relationship with prognosis, we compared the difference in MET expression between cancer tissue and healthy pancreatic tissue using the transcriptome data obtained from the public databases The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEX)

Summary

A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer

Reviewed by: Massimo Fantini, Precision Biologics, Inc., United States Pierpaolo Correale, Azienda Ospedaliera ’Bianchi-Melacrino-Morelli’, Italy. Zhan Q (2021) A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer. Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the United States and has a 5-year survival rate of

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT