Abstract 413: Targeting IL-6 as a preventive and therapeutic strategy for K-ras mutant lung cancer
Authors: Caetano Mauricio S. , Cumpian Amber M. , Gong Lei , Chang Seon H. , Zhang Huiyuan , Kadara Humam N. , Sternberg Cinthya , Ferreira Carlos G. , Watowich Stephanie S. , Moghaddam Seyed J. 
Published: August 2015

Worldwide, lung cancer (LC) leads in cancer mortality and cigarette smoking (CS) is its principal cause. Activating mutations of K-ras are one of the most common alterations in LC and are associated with CS exposure. However, several studies have shown that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have a higher risk of developing LC when compared to smokers without COPD. These facts suggest a strong link between COPD-type inflammatory lung microenvironment and K-ras mutant lung cancer. Unfortunately, attempts to directly target K-ras have thus far failed, clearly stating the need for new approaches to bring clinical benefits to patients with this undrugabble profile. Using a conditional K-ras induced lung cancer mouse model (CC-LR) we showed that K-ras mutant lung tumors have intrinsic inflammatory characteristics, and a bacterial lysate-induced COPD-like airway inflammation promotes lung cancer in this model. This was associated with release of the cytokine IL-6 and activation of the IL-6-responsive transcription factor STAT3. We showed that genetic ablation of IL-6 in this model results in a significant tumor reduction indicating an essential role for IL-6/STAT3 pathway in lung cancer promotion and introducing IL-6 as a druggable target for K-ras mutant lung tumor. Therefore, we blocked IL-6 using a monoclonal anti-IL-6 immunotherapy in our K-ras mutant model. Six week old CC-LR mice were injected intraperitoneally with 20 mg/kg dose of an anti-IL-6 monoclonal IgG1 antibody twice a week for eight weeks, while been exposed to the aerosolized bacterial lysate once weekly for 8 weeks. Anti-IL-6 therapy not only inhibited intrinsic lung cancer development by ∼78%, but also inhibited the tumor promoting effect of the COPD-like airway inflammation. It also decreased the expression of P-STAT3, proliferation marker, Ki67, and pro-angiogenic factors: VEGF, MMP-9 and CD31 in lung tissue. qPCR analysis of lung tissues from anti-IL-6 treated mice showed a decrease in Arginase1, FIZZ1, FOXP3, and IL-17 expression, with increased expression of Th1 markers, IFNγ and TBx21. Flow cytometry analysis of total lung inflammatory cells in CC-LR mouse showed a significant increase in the population of tumor associated macrophages (TAMs) during tumor progression from age 6 to 14 weeks, and COPD-like inflammation induced an increase in myeloid derived suppressor cell (MDSCs) population. Interestingly, we found a significant decrease in TAMs and MDSCs population after anti-IL-6 treatment. Taken together, we conclude that IL-6 blockade not only has cell intrinsic effect in K-ras mutant tumors but also edit the lung microenvironment toward an anti-tumor phenotype. Therefore, we propose pharmacological targeting of IL-6 alone or in combination with conventional cytotoxic therapy, or other targeted therapies for prevention and treatment of lung cancer patients with K-ras mutation.

Citation Format: Mauricio S. Caetano, Amber M. Cumpian, Lei Gong, Seon H. Chang, Huiyuan Zhang, Humam N. Kadara, Cinthya Sternberg, Carlos G. Ferreira, Stephanie S. Watowich, Seyed J. Moghaddam. Targeting IL-6 as a preventive and therapeutic strategy for K-ras mutant lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 413. doi:10.1158/1538-7445.AM2015-413