Introduction: Lung cancer is one of the leading cause of cancer death worldwide, with an estimate incidence of about 2 million new cases per year. Among all lung cancers, non-small-cell lung cancer (NSCLC) is the most frequent (nearly 85%) with a 5-year survival of about 25% when all stages are considered.NSCLCs are frequently mutated in KRAS or STK11/LKB1 and co-mutation is often reported. Considering the key role of STK11/LKB1 in controlling cell metabolism, we hypothesized that NSCLC harboring mutations in this gene could be vulnerable to metabolic stresses. Different studies in the last years have highlighted how is possible to interfere with cancer metabolism using metformin and caloric restriction.Our work aimed at investigating the role of metabolic stress in determining response to chemotherapy and immunotherapy in LKB1 mutated NSCLC model.

Methods: For isolation of cell lines with the genetic backgrounds, nodules from lungs of KRASG12D/LKB1wt and KRASG12D/LKB1mut transgenic mice were used. Stabilized cell lines were then inoculated intramuscularly in immunocompetent mice and treated with chemotherapy alone (cisplatin) or in combination with metformin and caloric restriction. Caloric restriction consisted of 36 hours of fasting every week for three weeks. Metformin was administered daily for the entire experiment while cisplatin was given once a week for three weeks.

Results: We started our in vivo experiments comparing the response of the tumors characterized by the mutation in KRASG12D or the co-mutation KRASG12D/LKB1mut. The results indicate that the addition of metformin and caloric restriction improve the activity of cisplatin in both tumors but a stronger effect was detected in tumors presenting the deletion of LKB1. In fact, only in the latter group, the effect of the combination lasted beyond the end of the treatment slowing down the tumor growth. The different combinations were well tolerated. Molecular analysis on tumor samples run in parallel are in progress.

Conclusion: Our in vivo preliminary studies confirm our hypothesis that the addition of the caloric restriction and metformin is able to improve the antitumor activity of the cisplatin without increasing the treatment toxicity in tumors characterized by the co-mutations of KRASG12D/LKB1mut. Further investigations are ongoing on the role of metabolic stress in addition to the immunotherapy (using anti PD-1 antibody as immunocheckpoint inhibitor).

Citation Format: Gloriana Ndembe, Mirko Marabese, Ilenia Intini, Alessandra Fabbri, Massimo Moro, Mario Occhipinti, Elisa Sottotetti, Giuseppe Lo Russo, Monica Ganzinelli, Massimo Broggini. The effect of metabolic alterations on chemo-immunotherapy response in non-small-cell lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2380.