Abstract Smokers with chronic obstructive pulmonary disease (COPD) face a 3-10-fold increased risk of developing lung cancer. In COPD patients, KRAS-mutant lung adenocarcinoma (KM-LUAD) is the most common subtype of lung cancer. Current treatments for KM-LUAD are often ineffective, further warranting novel preventative and therapeutic strategies. 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 using a genetic mouse model of KM-LUAD, CCSPCre/LSL-KRASG12D (CC-LR), 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-like inflammation. An initial short-term dose-finding study using ascending doses (25, 50, and 100 mg/kg) of TTI-101, a selective STAT3 inhibitor, revealed the strongest STAT3 inhibition (assessed by pY-STAT3 IHC and Luminex assay) at 100 mg/kg. Therefore, the remainder of this study was conducted using this dose. At ten weeks of age, following the NTHi lysate exposure, the mice were administered TTI-101 (100 mg/kg) or the vehicle control by oral gavage daily for 4 weeks. Upon the completion of treatment, blood, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for blood chemistry, histopathology, and inflammation and tumor burden. Additionally, we collected the small intestine, liver and kidneys for assessments of potential organ toxicity. TTI-101 treatment resulted in no significant weight changes or evidence of systemic toxicity. NTHi exposure induced COPD-type neutrophilic dominant inflammation in the vehicle-treated cohort, which was significantly reduced following the treatment with TTI-101 (∼2-fold; p 0.0001). Moreover, TTI-101 significantly reduced lung tumor burden (∼1.4-fold; p0.0001), along with expressions of the proinflammatory cytokine IL-17A and the potent neutrophil chemoattractant CXCL1, both of which we have previously shown to promote the development of lung cancer. PD1 expression was also significantly reduced relative to controls, consistent with enhanced immune activation as well as the reprogramming of the tumor immune microenvironment toward an antitumor phenotype. Collectively, these findings highlight STAT3 inhibition as a potential strategy to prevent KM-LUAD in patients with COPD. This abstract is funded by: NCI, NIH and the Department of Health and Human Services under contract No. 75N91019D00021/75N91022F00002
Friedman et al. (Fri,) studied this question.