Linking Serine/Glycine Metabolism to Radiotherapy Resistance

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.

The Differential Metabolic Response of Oral Squamous Cell Carcinoma Cells and Normal Oral Epithelial Cells to Cisplatin Exposure

“…In some tumors, the activation of de novo serine/glycine biosynthesis is considered to be the main factor of tumor pathogenesis, poor prognosis, and treatment resistance. Inhibition of the de novo serine/glycine biosynthesis pathway provides a promising strategy for tumor therapy [ 29 ]. Inhibition of serine metabolism decreased H3K4 tri-methylation and promoted cisplatin resistance in gastric cancer [ 30 ].…”

Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches

“…The interplay between radiotherapy and the immune system is shown in Figure 3. [67][68][69][70][71][72] In the phase II AFT-16 trial (n ¼ 64), patients with stage III NSCLC received two cycles of atezolizumab, then they were restaged and, if not progressive, they received two more atezolizumab infusions followed by CCRT (without atezolizumab). Afterwards, patients received consolidation atezolizumab up to 1 year.…”

“…Gal-1 together with vascular endothelial growth factor (VEGF) receptors promote neoangiogenesis 69. RT increases also: the serine/glycine metabolism in the tumor microenvironment (TME), resulting in higher levels of interleukin 1b (IL-1b) and M2 macrophages,72 myeloid-derived suppressor cells in the TME71 and CD73 expression 115. Both RT and SBRT increase levels of T-regulatory cells and programmed deathligand 1 (PD-L1), impairing T-cell activation [116][117][118].…”

Metabolic response to radiation therapy in cancer

“…Interestingly, the levels of phosphoserine aminotransferase 1 (PSAT1), which converts 3‐phospho‐hydroxypyruvate and glutamate to 3‐phospho‐serine and αKG, have been shown to increase after ionizing radiation (Figure 4), and targeting PSAT1 leads to radiation‐ and glutamine‐deprivation sensitivity in lung cancer cells 218 . Although there is a lack of studies on serine metabolism after radiation, the field is starting to recognize the role of SSP in redox metabolism 219–221 …”