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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Metformin | Research

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

Authors: Gloriana Ndembe, Ilenia Intini, Massimo Moro, Chiara Grasselli, Andrea Panfili, Nicolò Panini, Augusto Bleve, Mario Occhipinti, Cristina Borzi, Marina Chiara Garassino, Mirko Marabese, Simone Canesi, Eugenio Scanziani, Gabriella Sozzi, Massimo Broggini, Monica Ganzinelli

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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 chemotherapy or chemo-immunotherapy, both as standalone regimens and in combination with metformin and CR.

Results

Our preclinical results indicate that in NSCLC KRAS^mut/LKB1^mut tumors, metformin and CR do enhance the response to chemo and chemo-immunotherapy, inducing a metabolic stress condition that these tumors are not able to overcome. Analysis of immune infiltrating cells did not bring to light any strong correlation between the TME immune-modulation and the tumor response to metformin and CR.

Conclusion

Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress.

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Title: Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy
Authors: Gloriana Ndembe
Ilenia Intini
Massimo Moro
Chiara Grasselli
Andrea Panfili
Nicolò Panini
Augusto Bleve
Mario Occhipinti
Cristina Borzi
Marina Chiara Garassino
Mirko Marabese
Simone Canesi
Eugenio Scanziani
Gabriella Sozzi
Massimo Broggini
Monica Ganzinelli
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Metformin
NSCLC
NSCLC
Cytostatic Therapy
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-023-02933-5

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