Linking Serine/Glycine Metabolism to Radiotherapy Resistance

SIMPLE SUMMARY: Hyperactivation of the de novo serine/glycine biosynthesis across different cancer types and its critical contribution in tumor initiation, progression, and therapy resistance indicate the relevance of serine/glycine metabolism-targeted therapies as therapeutic intervention in cancer. In this review, we specifically focus on the contribution of the de novo serine/glycine biosynthesis pathway to radioresistance. We provide a future perspective on how de novo serine/glycine biosynthesis inhibition and serine-free diets may improve the outcome of radiotherapy. Future research in this field is needed to better understand serine/glycine metabolic reprogramming of cancer cells in response to radiation and the influence of this pathway in the tumor microenvironment, which may provide the rationale for the optimal combination therapies. ABSTRACT: The activation of de novo serine/glycine biosynthesis in a subset of tumors has been described as a major contributor to tumor pathogenesis, poor outcome, and treatment resistance. Amplifications and mutations of de novo serine/glycine biosynthesis enzymes can trigger pathway activation; however, a large group of cancers displays serine/glycine pathway overexpression induced by oncogenic drivers and unknown regulatory mechanisms. A better understanding of the regulatory network of de novo serine/glycine biosynthesis activation in cancer might be essential to unveil opportunities to target tumor heterogeneity and therapy resistance. In the current review, we describe how the activation of de novo serine/glycine biosynthesis in cancer is linked to treatment resistance and its implications in the clinic. To our knowledge, only a few studies have identified this pathway as metabolic reprogramming of cancer cells in response to radiation therapy. We propose an important contribution of de novo serine/glycine biosynthesis pathway activation to radioresistance by being involved in cancer cell viability and proliferation, maintenance of cancer stem cells (CSCs), and redox homeostasis under hypoxia and nutrient-deprived conditions. Current approaches for inhibition of the de novo serine/glycine biosynthesis pathway provide new opportunities for therapeutic intervention, which in combination with radiotherapy might be a promising strategy for tumor control and ultimately eradication. Further research is needed to gain molecular and mechanistic insight into the activation of this pathway in response to radiation therapy and to design sophisticated stratification methods to select patients that might benefit from serine/glycine metabolism-targeted therapies in combination with radiotherapy.