Abstract 3714: Muc5ac plays an essential role in promotion of k-ras mutant lung cancer

Abstract

Abstract Worldwide, lung cancer is the leading cause of cancer mortality, and cigarette smoking (CS) is its principal cause. However, several studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer (3 to 10-fold) compared to smokers with comparable cigarette exposure but without COPD. Importantly, among smokers with COPD, even following withdrawal of cigarette smoke, inflammation persists and lung function continues to deteriorate as does the increased risk of lung cancer. These facts suggest a strong link between COPD-related lung inflammation and lung cancer, however, the precise mechanistic link is not known. Mucociliary dysfunction and mucin hyperproduction are important features of COPD with inflammation being the major trigger. Interestingly, lung cancer with mucin overexpression has higher malignancy potential and poor prognosis, which around 76% having mutations in K-ras oncogene, the most frequent oncogenic mutation in lung adenocarcinoma. Taken these together, we hypothesized that mucins contribute to promotion of K-ras mutant lung cancer by inflammation. Here we first investigated whether Muc5ac, predominant airway mucin that plays a primary role in inflammatory lung diseases, is predictive of clinical outcome in KRAS-mutant human lung adenocarcinomas. We determined Muc5ac mRNA expression by array analysis of 150 lung adenocarcinomas from patients that did not received neoadjuvant therapy and we found that, Muc5ac mRNA level was a significant predictor of poor disease-free survival in KRAS-mutant lung adenocarcinomas. We have further found increased mucin and high expression of Muc5ac in lung tumor tissues of the mice with airway specific expression of a mutant form of K-ras (CC-LR mice). Then, we crossed previously developed Muc5ac knockout (KO) mice to CC-LR mice in order to develop a K-ras mutant lung cancer mouse model with lack of Muc5ac (CC-LR/Muc5ac KO mice). This resulted in a significant tumor reduction by ~54% (2.2-fold) in lung of CC-LR/Muc5ac KO mice compared to age and sex matched control CC-LR mice. Lung inflammation was evaluated by analysis of bronchoalveolar lavage fluid and revealed a significant reduction (3-fold) in number of macrophages, and levels of IL-6 and IL-17 in CC-LR/Muc5ac KO mice compared to CC-LR control mice. Immunohistopathological analysis of lung sections confirmed lower inflammation, decreased tumor number and size, less adenomatous lesions, and reduced tumor cell proliferation and angiogenesis in CC-LR mice with lack of Muc5ac compared to control CC-LR mice. Our experimental results suggest that Muc5ac has an essential role in promotion of K-ras mutant lung cancer through autocrine cell intrinsic and paracrine immune cell mediated mechanisms. Citation Format: Misha Umer, Amber M. Cumpian, Nasim Khosravi, Zoulikha Azzegagh, Maede Mohebnasab, Mauricio S. Caetano, Edwin J. Ostrin, Ignacio I. Wistuba, Burton Dickey, Humam Kadara, Christopher M. Evans, Seyed J. Moghaddam. Muc5ac plays an essential role in promotion of k-ras mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3714. doi:10.1158/1538-7445.AM2017-3714