Stk11-KO Mouse

STK11, also known as LKB1, encodes the protein liver kinase B1, a serine/threonine kinase involved in multiple physiological processes. It is crucial for regulating cellular metabolism, cell polarity, and the DNA damage response. As a tumour suppressor, it classically acts through the AMP-activated protein kinase-mediated inhibition of the mammalian target of rapamycin signalling pathway [4].

In non-small cell lung cancer (NSCLC), STK11 mutations are associated with various outcomes. STK11-deficient phenotype rather than mutation status can better stratify immune checkpoint inhibitor (ICB) outcomes. STK11-def tumours show lost or reversed survival benefit of ICB compared to chemotherapy, while STK11-prof tumours maintain the benefit. This is related to STING/interferon-I signalling perturbation and CD8+ T-cell dysfunction in STK11-def tumours [1]. In lung adenocarcinoma, concurrent mutations in STK11 and KEAP1 promote ferroptosis protection and SCD1 dependence [2]. Also, in STK11/LKB1 mutant NSCLC, targeting AXL can restore PD-1 blockade sensitivity by expanding TCF1+ CD8 T cells [3].

In summary, STK11 is essential for multiple physiological functions, especially in metabolic and tumour-suppressing pathways. Research on STK11, often through genetic models like KO/CKO mouse models in pre-clinical studies, has significantly contributed to understanding its role in NSCLC and other diseases, offering potential therapeutic targets and strategies for better patient outcomes.

References:

1. Li, Anlin, Wang, Yuanyuan, Yu, Zhixin, Zhang, Li, Hong, Shaodong. 2023. STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC. In Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 18, 1714-1730. doi:10.1016/j.jtho.2023.07.020. https://pubmed.ncbi.nlm.nih.gov/37495171/

2. Wohlhieter, Corrin A, Richards, Allison L, Uddin, Fathema, Sen, Triparna, Rudin, Charles M. . Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer. In Cell reports, 33, 108444. doi:10.1016/j.celrep.2020.108444. https://pubmed.ncbi.nlm.nih.gov/33264619/

3. Li, Huiyu, Liu, Zhida, Liu, Longchao, Minna, John D, Brekken, Rolf A. 2022. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells. In Cell reports. Medicine, 3, 100554. doi:10.1016/j.xcrm.2022.100554. https://pubmed.ncbi.nlm.nih.gov/35492873/

4. Zyla, Roman E, Hahn, Elan, Hodgson, Anjelica. 2021. Gene of the month: STK11. In Journal of clinical pathology, 74, 681-685. doi:10.1136/jclinpath-2021-207906. https://pubmed.ncbi.nlm.nih.gov/34479873/