Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy

作者：Gloriana Ndembe, Ilenia Intini, Massimo Moro, Chiara Grasselli, Andrea Panfili, Nicolò Panini, Augusto Bleve, Mario Alberto Occhipinti, Cristina Borzi, Marina Chiara Garassino, Mirko Marabese, Simone Canesi, Eugenio Scanziani, Gabriella Sozzi, Massimo Broggini, Monica Ganzinelli · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2024 · DOI：10.1186/s13046-023-02933-5 · 被引用次数：19 · 研究领域：Metabolism, Diabetes, and Cancer、Cancer Risks and Factors、Cancer, Lipids, and Metabolism

Abstract Background About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1 , a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from “cold” to “hot”. Given the poor therapeutic response of KRAS mut / LKB1 mut patients, and the role of LKB1 in cell metabolism, we examined whether the addition of metformin and CR enhanced the response to chemo or chemo-immunotherapy in LKB1 impaired tumors. Methods Mouse cell lines were derived from lung nodules of transgenic mice carrying KRAS G12D with either functional LKB1 (KRAS G12D /LKB1 wt ) or mutated LKB1 (KRAS G12D /LKB1 mut ). Once stabilized in vitro, these cell lines were inoculated subcutaneously and intramuscularly into immunocompetent mice. Additionally, a patient-derived xenograft (PDX) model was established by directly implanting tumor fragments from patient into immunocompromised mice. The mice bearing these tumor models were subjected to treatment with...