Abstract 2613: Chronic NNAL exposure, mimicking tobacco use in humans, deactivates LKB1 and promotes tumor progression in non-small cell lung cancer

Abstract Background: LKB1 loss-of-function is one key oncogenic event in lung cancer. Clinical data suggest that LKB1 loss-of-function is associated with patients’ smoking status. We recently discovered that NNAL, a major metabolite of a tobacco specific carcinogen NNK, rapidly induces LKB1 phosphorylation and its loss-of-function via the β-AR/PKA signaling pathway in an isomer-dependent manner in human lung cancer cells. Such an acute exposure, however, only resulted in moderate enhancement in lung cancer cell migration and chemoresistance. Here we characterized the effects of chronic NNAL exposure, better mimicking human tobacco use, on LKB1 and tumor progression in NSCLC in vitro and in vivo. Methods and Results: Human NSCLC cells with wild type LKB1 (H1299 and H1975) were cultured in the presence of 1 nM NNAL for 3, 6 and 12 months. LKB1 and its signaling pathways were characterized with phenotypes evaluated, including cell proliferation, migration, and chemoresistance. NNAL chronic exposure in lung cancer cells, mimicking its chronic exposure among smokers, resulted in more prominent LKB1 phosphorylation and the deactivation of its signaling, cell migration, and chemoresistance even in the absence of NNAL, indicating the long-lasting LKB1 loss-of-function. These observations were confirmed in a lung cancer xenograft model. More importantly, human lung cancer tissues revealed elevated LKB1 phosphorylation in comparison to the paired normal lung tissues. Conclusion: These results suggest that LKB1 loss-of-function in human lung cancer could be extended to its phosphorylation, which may be mediated by NNAL from tobacco smoke in an isomer-dependent manner via the β-AR/PKA signaling pathway. Citation Format: Tengfei Bian, Lingtao Jin, Chengguo Xing. Chronic NNAL exposure, mimicking tobacco use in humans, deactivates LKB1 and promotes tumor progression in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2613.