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Abstract Introduction Reducing glucose and growth factor provision to cancer cells through in vitro starvation (STV) or in vivo fasting/fasting-mimicking diets (FMDs) delays tumor progression and prolongs survival in tumor-bearing mice. More recently, cyclic FMD has been shown to be safe and associated with promising metabolic and immunomodulatory effects in cancer patients. However, cyclic fasting and FMD only retard tumor progression, but they do not result in tumor cure when used alone. Here, we hypothesized that tumor cells exposed to STV activate Fatty Acid Oxidation (FAO) as an alternative metabolic pathway that could be responsible for primary or acquired tumor cell resistance to STV. Methods We investigated the effects of FAO inhibition (FAOi) in combination with STV on the proliferation and survival of human or murine cell lines of Triple Negative Breast Cancer (TNBC) (n=16), HR+HER2- breast cancer (n=3), colorectal (n=1), pancreatic (n=1) and lung cancer (n=1), as well as of non-transformed human epithelial cells (n=3). STV consisted of a 50% reduction of extracellular glucose and serum in cell growth media. To inhibit FAO, we used the Carnitine Palmitoyl transferase 1 inhibitor Etomoxir or ST1326. Results STV+FAOi resulted in cooperative or highly synergistic antiproliferative effects in all cancer models tested, but not in normal cells. At longer time points, STV+FAOi enhanced tumor cell death through the activation of apoptosis. Depending on the specific tumor type, the cooperative effects of STV and FAOi were mostly mediated by glucose or fatty acid restriction in the STV medium. On the other hand, the reduction of extracellular growth factors did not affect cell proliferation upon STV+FAOi combination. Intracellular ATP levels were reduced upon cell exposure to the combined treatment at later time points. However, the supplementation of several sources of ATP, such as glutamine or TCA cycle intermediates, to tumor cells did not rescue the antitumor effects of STV+FAOi, thus excluding the strong impact of this combination on tumor cell bioenergetics. On the other hand, STV+FAOi caused an excessive intracellular antioxidant response, which in part mediated the synergistic effects of STV+FAOi. Indeed, Etomoxir alone mildly increased the NADPH/NADP+ ratio, whereas its combination with STV resulted in a remarkable increase of this ratio. In parallel, combining the antioxidant molecules n-acetylcysteine (NAC) and reduced glutathione (GSH) with FAOi caused antitumor effects that recapitulate those produced by STV+FAOi treatment. Conclusions FAO is a potential resistance mechanism to nutrient starvation, with broad antitumor activity in different models of murine and human malignancies, but not in normal cells. In cancer cells, FAOi synergizes with STV by strongly affecting intracellular redox balance. FAOi is a new strategy that should be explored in future preclinical in vivo experiments and in clinical studies to potentiate the antitumor effects of nutrient starvation in solid malignancies. Citation Format: Marzia Santamaria, Beatrice Cantarelli, Arta Ajazi, Chiara Milanese, Giulia Salvadori, Pier Giorgio Mastroberardino, Paola Antonia Corsetto, Giancarlo Pruneri, Filippo De Braud, Claudio Vernieri. Targeting fatty acid oxidation to boost the anti-tumor effects of nutrient starvation in solid malignancies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB294.
Santamaria et al. (Fri,) studied this question.