ESTRO 2024 - Abstract Book

S5218

Radiobiology - Microenvironment

ESTRO 2024

Targeting serine/glycine metabolism improves radiotherapy response in Non-Small Cell Lung Cancer

Anaís Sánchez Castillo 1 , Elien Heylen 2 , Judith Hounjet 1 , Kim G. Savelkouls 1 , Natasja G. Lieuwes 3 , Rianne Biemans 3 , Ludwig J. Dubois 3 , Kobe Reynders 1,4 , Kasper M. Rouschop 1 , Rianne D.W. Vaes 1 , Kim De Keersmaecker 2 , Maarten Lambrecht 5 , Lizza E.L. Hendricks 6 , Dirk K.M. De Ruysscher 1 , Marc Vooijs 1 , Kim R. Kampen 1,2 1 GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Department of Radiation Oncology (MAASTRO), Maastricht, Netherlands. 2 Laboratory for Disease Mechanisms in Cancer, KU Leuven, and Leuven Cancer Institute (LKI), Department of Oncology, Leuven, Belgium. 3 GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Department of Precision Medicine, The M-Lab, Maastricht, Netherlands. 4 KU Leuven, and Leuven Cancer Institute (LKI), Department of Oncology, Experimental Radiation Oncology, Leuven, Belgium. 5 University Hospital Leuven, Department of Radiation Oncology, Leuven, Belgium. 6 GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Department of Pulmonology, Maastricht, Netherlands Lung cancer is the most lethal cancer and about 85% of lung cancers are classified as non-small cell lung cancer (NSCLC), where therapy resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer cells and metabolic vulnerabilities of cancer cells are attractive targets to be exploited to improve the therapeutic efficacy and cure rates. NSCLC tumors exhibit upregulation of serine/glycine (ser/gly) synthesis metabolic pathway, which has been associated with NSCLC pathogenesis, poor outcome, and treatment resistance (1, 2). Furthermore, cancer cell-derived serine and glycine pathway metabolites can influence the tumor microenvironment (3, 4). The role of ser/gly metabolism in response to radiotherapy (RT) treatment remains largely unknown. We propose that the activation of ser/gly synthesis pathway plays a crucial role in supporting the survival and recovery of cancer cells upon RT treatment by providing ATP, nucleotides, and antioxidants (5). Therefore, the inhibition of ser/gly synthesis pathway might be a promising strategy for therapeutic intervention in combination with RT. Our lab has identified the repurposed compound sertraline as a potent inhibitor of the bidirectional conversion of serine to glycine by targeting the enzyme SHMT1/2 (6). In this study, we aimed to investigate the effects of RT in combination with sertraline on NSCLC tumor and systemic metabolic responses. Purpose/Objective:

Material/Methods:

We performed targeted metabolomics on 37 blood plasma samples of stage I/III NSCLC patients before and during RT schedule.

We landscaped RT responses using 13 C 6 -Glucose metabolic tracing in a panel of NSCLC cell lines. The protein expression of SHMT2, the main cancer-related enzyme responsible for ser/gly conversion, was analyzed in response to RT using flow cytometry and immunoblot. Additionally, we explored the efficacy of combining RT with serine/glycine conversion inhibitor sertraline, by performing proliferation, clonogenic and limiting dilution sphere assays in vitro. Next, we determined the downstream cellular effect on reactive oxygen species (ROS) by flow cytometry. The impact of the combination of sertraline and RT in vivo was assessed using the immune suppressive Lewis Lung carcinoma (LLC) model in immunocompetent C57BL/6 mice. In this context, we analyzed circulating ser/gly pathway metabolites in blood serum and tumor fluidics, cytokines levels in the tumor microenvironment and expression of immune cell markers.