19IN - Metabolic Consequences of Arginine Deprivation in ASS1-Deficient Cancers

Date 06 March 2018
Event TAT 2018 - Targeted Anticancer Therapies
Session Metabolic targets
Presenter Brian Van Tine
Citation Annals of Oncology (2018) 29 (suppl_3): iii1-iii6. 10.1093/annonc/mdy046
Authors B. Van Tine
  • -, Washington University in Saint Louis, 63110 - St. Louis/US


Argininosuccinate Synthetase 1 (ASS1) is silenced in ∼90% of sarcomas. Loss of this urea cycle enzyme causes cells to become dependent upon extracellular arginine for continued cell growth and proliferation. Upon arginine starvation, ASS1(-) sarcoma cells undergo autophagy, increase their glutamine dependence and undergo growth arrest. In order to identify potentially exploitable synthetic lethal targets arising from the induction of autophagy following arginine deprivation, we investigated the metabolic alterations caused by arginine deprivation resulting from treatment with PEGylated arginine deiminase (ADI-PEG20). Mass spectroscopy was performed and revealed a significant increase in the level of serine biosynthesis from glucose which resulted from the up regulation of PHGDH. When paired with ADI-PEG20 treatment, inhibition of serine metabolism results in significant cell death. With recent studies showing the importance of serine biology in cancer, as well as recent generation of a small molecule PHGDH inhibitor to the rate limiting enzyme in serine biosynthesis, this newly identified synthetic lethality proves to be an exploitable therapeutic option for ASS1 deficient sarcomas.