Abstract 5075: Naproxen blocks spontaneous lung adenoma progression to adenocarcinoma in Kras-G12V mice

Abstract

Abstract The aim of the present study was to investigate the effects of a non-steroidal anti-inflammatory drug (NSAID), naproxen, on a spontaneous mouse model of lung adenocarcinoma. Lung cancer is the most frequently diagnosed cancer and the primary cause of cancer-related deaths worldwide. Inflammation plays an important role in the development and progression of lung and several other cancers. The association between NSAID use and lung cancer risk suggests a beneficial effect on patients’ lung cancer progression. Preventing lung cancer can help to significantly reduce cancer-related mortality. Compared with other NSAIDs, naproxen is relatively safer in terms of cardiovascular risk. Eight-week-old transgenic KrasG12V male and female mice (n=20) or littermate wild-type (n=5) mice were fed (AIN76A) diets containing naproxen (0 ppm or 400 ppm) in modified AIN76-A diet for 28 weeks. At 36 weeks of age, mice were euthanized. Lungs were collected and evaluated for lung tumor incidence and multiplicity, and were saved in formalin for histopathological identification of adenoma and adenocarcinoma. By 12 weeks of age, KrasG12V mice developed visible lung tumors that enlarged in size and progressed to adenocarcinoma by 24-36 weeks of age. Lung tumor incidence was observed in 100% of KrasG12V mice. Dietary administration of naproxen did not show any overt-toxicities. No significant changes were observed in body weight gain or any major organ’s (liver, kidney, and pancreas) gross morphology or weight in mice fed with naproxen compared with mice fed control diet. Due to reduced tumor burden, lungs of the naproxen-fed mice weighed less (230.6± 12.2 mg, p=0.019) (Mean±SEM) than those of the control group (384.0±68.1 mg). Importantly, mice fed control diet developed 19.8±0.96 total lung tumors (2.5±0.3 adenoma, 17.3±0.7 adenocarcinoma). The results suggest that naproxen inhibits total lung tumor formation by ~52% (9.4±0.85;p<0001) and adenocarcinoma by ~64% (6.1±0.6; p<0001), compared with control diet. However, we observed no significant difference in the number of adenomas in mice fed with control diet and mice fed naproxen diet. These data suggest that naproxen delays the progression of lung adenoma to adenocarcinoma. Biomarker analysis of lung tumors from mice exposed to naproxen showed significantly reduced tumor cell proliferation (PCNA, Cyclin D1) and increased apoptosis (p21, Caspase-3). These results support a chemopreventive role of naproxen in spontaneous-induced lung adenocarcinoma formation. (Supported by the Kerley-Cade Chair Endowment & partly by the NCI-PREVENT program HHSN261201500038i) Citation Format: Gaurav Kumar, Venkateshwar Madka, Craig Logsdon, Anil Singh, Nicole Stratton, Stanley Lightfoot, Altaf Mohammed, Chinthalapally V. Rao. Naproxen blocks spontaneous lung adenoma progression to adenocarcinoma in Kras-G12V mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5075.