Abstract 7311: Targeting STAT3 to prevent non-small cell lung cancer in patients with chronic obstructive pulmonary disease

Abstract Non-small cell lung cancer (NSCLC), primarily caused by cigarette smoking, is the leading cause of cancer-related deaths worldwide. Smokers with chronic obstructive pulmonary disease (COPD) face a 3-10 fold increased risk of developing NSCLC compared to smokers without COPD. Lung inflammation and functional deterioration persist in COPD patients, and the risk of developing NSCLC remains elevated. This notes the importance of targeting inflammatory pathways to prevent cancer progression. In COPD patients, lung adenocarcinoma (LUAD) is the most common subtype of NSCLC, with about 30% of cases featuring activating mutations in the Kirsten rat sarcoma viral (KRAS) oncogene. Current treatments for KRAS-mutant LUAD (KM-LUAD) are often ineffective, warranting novel preventive and therapeutic methods. Our group previously developed a COPD-like mouse model through weekly exposure to an aerosolized lysate of non-typeable Haemophilus influenzae (NTHi), a common airway colonizer in COPD patients. Using this model, we showed that COPD-like inflammation promotes KM-LUAD with an essential role for the pro-inflammatory cytokine, IL-6, and activation of signal transducer and activator of transcription 3 (STAT3). Here, we investigated the effects of STAT3 inhibition on KM-LUAD promotion by COPD. We utilized CCSPCre/LSL-KrasG12D (CC-LR) mice, a genetic model of LUAD that develops early-stage lung lesions starting at six weeks of age. Six-week-old CC-LR mice were exposed to aerosolized NTHi lysate or PBS weekly to induce COPD. At ten weeks of age, they received one of three doses (25, 50, or 100 mg/kg) of TTI-101, a selective STAT3 inhibitor, or vehicle control daily for 14 days by oral gavage. We then collected blood, bronchoalveolar lavage fluid (BALF), and lung tissues for complete blood counts, blood chemistry tests, tumor burden, inflammation analysis, and histopathology. Results indicated no significant weight changes or toxicity from TTI-101 treatment. NTHi exposure induced COPD-type neutrophilic inflammation in vehicle treated cohorts that was reduced following the treatment with TTI-101. Tumor burden, both multiplicity and area, also showed a significant decrease in TTI-101-treated mice. Inflammation and levels of tyrosine phosphorylated STAT3 (pY-STAT3) in lung tissues were significantly reduced post-treatment. These findings suggest that STAT3 contributes to KM-LUAD promotion in COPD and that its inhibition with TTI-101 may effectively prevent KM-LUAD associated with COPD. Further research will determine the effects of TTI-101 in preventing NSCLC promotion and identify candidate biomarkers that correlate with NSCLC development and the preventative efficacy of TTI-101. Funding: This project was funded by Federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under contract No. 75N91019D00021/75N91022F00002 Citation Format: Katherine E. Larsen, Leticia G. Hamana Zorrilla, T Kris Eckols, Moses M. Kasembeli, Michael J. Clowers, Avantika Krishna, Maria T. Grimaldo, Nastaran Karimi, Shanshan Deng, Vignesh Gunasekharan, Luisa M. Solis Soto, David J. Tweardy, Seyed Javad Moghaddam. Targeting STAT3 to prevent non-small cell lung cancer in patients with chronic obstructive pulmonary disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7311.