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Title: Mechanisms of Resistance to PHGDH Inhibitors in Cancer
Authors: Brian A. Van Tine
Affiliations: Barnes and Jewish Hospital, Washington University in St. Louis
Abstract: The identification of biomarkers specific to certain types of cancer has lead to the development of novel, targeted therapies. Targeting components of cellular metabolism has brought a variety of new treatments to the forefront. However, metabolic reprogramming within cancer cells allows cells to quickly acquire resistance to these treatments. 3-phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme of de novo serine biosynthesis, and has been shown to be elevated in a variety of cancers. Inhibitors of the enzymatic activity of PHGDH, including CBR-5884 and NCT-503, have shown promising effects in vitro, causing a decrease in cellular proliferation. However, these effects are minimal in vivo, suggesting that tumors that are otherwise susceptible to PHGDH inhibition can develop resistance to the inhibitors over time. This review will interrogate the role of PHGDH in the development and progression of cancer. With an understanding of the molecular mechanisms of PHGDH inhibition in cancer, we will then highlight mechanisms of resistance to PHGDH inhibition, and identify avenues for combatting PHGDH resistance for the development of more effective metabolic therapies.