Abstract 5843: Selective small molecule inhibitor of STAT3 suppresses tumor growth and improves immune checkpoint inhibitor efficacy in <i>KRAS</i> mutant lung cancer

Abstract KRAS mutant (KM) lung cancer is the most common molecular subtype of lung adenocarcinoma (LUAD) and is strongly associated with cigarette smoking. KM-LUAD has a poor prognosis as it is resistant to most chemotherapy and targeted therapies. Also, despite recent breakthroughs in development of KRAS inhibitors (KRASi) and immune checkpoint inhibitors (ICIs), only a small sub-population of patients benefit from these therapies and resistance eventually develops. Thus, an urgent unmet medical need exists for alternative strategies that can complement KRASi and/or ICI to improve responses. KM-LUAD is closely associated with tumor-promoting inflammation, particularly the activation of the IL-6/STAT3 pathway. We previously showed in KM-LUAD patients that higher levels of STAT3 mRNA was associated with worse disease-free survival, and that targeting IL-6 in the CCSPCre/LSL-KrasG12D (CC-LR) mouse model of KM-LUAD reduced STAT3 activation and lung tumorigenesis. In this study, we targeted STAT3 directly with a safe and selective small molecule STAT3 inhibitor, TTI-101, that currently is in Phase II studies for treatment of hepatocellular carcinoma and idiopathic pulmonary fibrosis. Starting at 14 weeks of age, when tumors are established, four groups of CC-LR mice (n= 9-16 per group) received TTI-101 alone (100 mg/kg by oral gavage daily), anti-PD-1 mAb alone (10 mg/kg intraperitoneally thrice weekly), TTI-101 plus anti-PD-1 mAb, or no treatment for four weeks. TTI-101 alone reduced lung surface tumor number (LSTN) by 39.5% (22.4 ± 12.0 LSTN; mean ± SD) compared to the no-treatment group (37.0 ± 12.8 LSTN; p=0.02; Welch’s ANOVA), while anti-PD-1 mAb alone failed to reduce LSTN (43.8 ± 17.0 LSTN; p=ns). Notably, the combination of anti-PD-1 with TTI-101 further decreased LSTN by 46.4% (12.0 ± 5.7 LSTN) compared to TTI-101 alone (22.4 ± 12.0 LSTN; p=0.04) and by 72.6% (12.0 ± 12.0 LSTN) compared to anti-PD-1 mAb alone (43.8± 17.0 LSTN; p=0.0002). Daily monitoring indicated no significant weight changes or toxicity from either TTI-101 or anti-PD-1 mAb treatment. Thus, STAT3 inhibition using TTI-101, either alone or in combination with anti-PD-1, is a promising new strategy for treating KM-LUAD. Funding support: This project has been funded by an NIH/NCI R01 grant (1R01CA279452-01A1) awarded to SJM, DJT, and FS. AZ was partly supported by the Carl B. and Florence E. King Foundation Summer Program in Biomedical Sciences, MD Anderson Cancer Center. Citation Format: Shanshan Deng, Kris Eckols, Moses Kasembeli, Katherine E. Larsen, Nastaran Karimi, Michael J. Clowers, Anthony Zhang, Leticia G. Hamana Zorilla, Luisa M. Solis Soto, Imran Alibhai, Sofia de Achaval, Ferdinandos Skoulidis, David J. Tweardy, Seyed Javad Moghaddam. Selective small molecule inhibitor of STAT3 suppresses tumor growth and improves immune checkpoint inhibitor efficacy in KRAS mutant lung cancer [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 5843.