IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis.

Gavin D Brooks,Prudence A Russell,Stefan Rose-John,Saleela Ruwanpura,Alistair Miller,Brendan J Jenkins,Walter Ferlin,Sultan Alhayyani,Louise Mcleod

doi:10.1158/0008-5472.can-15-2388

Abstract

Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis. Malignant growths in the gp130(F/F):Kras(G12D) model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras(G12D) mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 trans-signaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.

Highlights

Lung adenocarcinoma is the most common ($40%) form of lung cancer, the number one cancer killer worldwide, which accounts for approximately 1.5 million deaths annually [1]
Extensive adenomatous hyperplasia (AAH), diffuse adenocarcinoma in situ (AIS), and areas of invasive adenocarcinoma were observed throughout the lungs of gp130F/F:KrasG12D mice, and there was an overall significant 2-fold increase in the area of lung parenchyma affected by these lesions in gp130F/F:KrasG12D compared with KrasG12D mice (Fig. 1A and B)
In support of the exacerbated lung tumorigenesis in gp130F/F:KrasG12D mice, immunohistochemical evaluation with the alveolar epithelial type II cell marker transcription factor (TTF)-1, which is used for the clinical diagnosis of lung adenocarcinoma [41], indicated a significant 2-fold increase in the number of TTF1–positive (TTF-1þ) cells in gp130F/F:KrasG12D compared with KrasG12D lungs (Fig. 1C and D)

Summary

Introduction

Lung adenocarcinoma is the most common ($40%) form of lung cancer, the number one cancer killer worldwide, which accounts for approximately 1.5 million deaths annually [1]. Lung adenocarcinoma is often diagnosed at an advanced stage, and current treatment options largely comprising surgery, chemotherapy, and/or radiotherapy remain associated with a high risk of tumor reoccurrence and poor patient survival rates The identification of EGFR-activating mutations in 15% to 20% of lung adenocarcinoma patients, mainly nonsmoking Asian females, has paved the way for targeted therapy with tyrosine kinase inhibitors [3]. Effective therapies for lung adenocarcinoma with more typical mutation profiles, namely those associated with cigarette smoking, which accounts for 80% to 90% of lung adenocarcinoma cases [2], remain to be identified, highlighting the need for a better understanding of the molecular and genetic alterations that promote the initiation and progression of lung adenocarcinoma. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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Results

Conclusion