Neutralizing monoclonal antibody against Dickkopf2 impairs lung cancer progression via activating NK cells

Tianli Shen,Tianli Shen,Xuejun Sun,Ju Qiao,Zhengxi Chen,Zhengxi Chen,Zhengxi Chen,Qian Xiao

doi:10.1038/s41420-019-0204-4

Abstract

Adenomatous polyposis coli (APC) and KRAS proto-oncogene (KRAS) mutations frequently co-occur in non-small cell lung cancer. Inactivating APC mutations in colorectal carcinoma has been well characterized, leading to the approaches targeting on dysregulated APC pathway. However, it remains undetermined whether such approaches are also applicable to non-small cell lung cancer patients harboring similar mutations of APC. Dickkopf-related protein 2 (DKK2) is a Wnt antagonist. Our previous study has proved that anti-DKK2 antibody 5F8 suppressed the growth of colorectal carcinoma with APC mutations, illustrating a new target agent of APC-mutated tumors. This study aimed to investigate the potential of applying anti-DKK2 antibody to non-small cell lung cancer with APC mutations. We found significant upregulation of Dkk2 expression in APC-mutated lung cancers. Administration of DKK2 antibody inhibited cancer growth via modulating tumor immune microenvironment in lung cancer mouse models. Our study provided strong evidence supporting APC mutations-directed applications of anti-DKK2 targeted therapy in a wide range of cancer types, including lung cancer.

Highlights

Lung cancer is one of the leading causes of cancerrelated death, resulting in more than 1 million deaths worldwide annually[1,2]
Upregulation of Dkk[2] expression is found in APCmutated group compared with APCwt group (Fig. 1a). This suggests that Dickkopf-related protein 2 (DKK2) might have an important role in these non-small cell lung cancer (NSCLC) with Adenomatous polyposis coli (APC) mutation
DKK2 expression is present in both human NSCLC with APC mutation and mice lung tumors caused by Apc loss

Summary

Introduction

Lung cancer is one of the leading causes of cancerrelated death, resulting in more than 1 million deaths worldwide annually[1,2]. Lung cancer can be histologically classified into four major categories: lung adenocarcinoma, squamous cell carcinoma (SCC), large cell carcinoma, comprising non-small cell lung cancer (NSCLC), and small cell[3,4,5,6,7,8,9] carcinoma of the lung. Among these categories, NSCLC is more common (~80%). The canonical Wnt/β-catenin pathway is initiated by two types of cell-surface receptors: low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6, respectively), and Frizzled proteins[18].

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