Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition

Abstract

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo , genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE:Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These fi ndings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.

Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

“…While the combination of PH755 with a serine and glycine depleted diet could be beneficial in many cancer types, tumours arising in an environment naturally low in serine could benefit from PH755 treatment without the requirement for additional dietary intervention 23 . As shown recently, treatment with PH755 was effective in limiting serine synthesis and tumour growth of metastases in the brain, where environmental serine and glycine levels are low 31 . Furthermore, tumours carrying other genetic alterations that lead to resistance to dietary serine depletion, such as p53 or KRAS mutations, may be sensitive to the combination therapy described here.…”

“…More recently, a highly potent, selective and reversible PHGDH inhibitor, PH755, has been reported to prevent the flux of labelled glucose into serine in LPS stimulated macrophages and improve the survival of mice exposed to LPS-induced endotoxemia 30 . This inhibitor has also been shown to be effective to limit tumour growth in vivo 24 , 31 . In this study we examine the cooperation between serine and glycine starvation (-SG) and PHGDH inhibition (PHGDHi), demonstrating a reduction of tumour cell growth in vitro and in vivo.…”

Metabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis

“…The microenvironment of the brain is known to contain lower amounts of serine and glycine than the plasma [ 121 , 122 ]. Recently, PHGDH was shown to be a major determinant of brain metastasis in multiple human cancer types and preclinical models of breast cancer and melanoma ( Figure 6 A) [ 123 ]. In this particular study, genetic and pharmacological inhibition of PHGDH attenuated brain metastasis, indicating that PHGDH inhibitors may be useful in the treatment of brain metastasis [ 123 ].…”

PHGDH as a mechanism for resistance in metabolically-driven cancers

“…PHGDH has been demonstrated to be upregulated in a wide variety of biologically distinct cancers, including colorectal cancer [ 33 ] , gastric cancer [ 34 ] , breast cancer [ 35 , 36 ] , melanoma [ 37 ] , Ewing’s sarcoma [ 38 ] , cervical cancer [ 39 ] , pancreatic cancer [ 40 ] , thyroid cancer [ 41 ] , colon cancer [ 42 ] , lung adenocarcinoma [ 43 ] , and non-small cell lung cancer [ 44 ] . Furthermore, increased PHGDH expression has been linked to brain metastasis [ 45 ] .…”

“…Furthermore, in a study in brain metastases, increased PHGDH expression was correlated with increased metastatic potential to the brain. Interestingly, in this study, inhibiting PHGDH attenuated metastasis without affecting extra-cranial tumour growth, suggesting that the consequences of increased PHGDH expression were directly related to upregulated metastasis [ 45 ] . Finally, this study highlighted the limited environmental availability of serine in the brain, demonstrating the subsequent reliance on de novo serine biosynthesis [ 45 ] .…”