Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells

Mihir B. Doshi, Namgyu Lee, Tenzin Tseyang, Olga Ponomarova, Hira Lal Goel, Meghan Spears, Rui Li, Lihua Julie Zhu, Christopher Ashwood, Karl Simin, Cholsoon Jang, Arthur M. Mercurio, Albertha J. M. Walhout, Jessica B. Spinelli and Dohoon Kim ()
Additional contact information
Mihir B. Doshi: University of Massachusetts Chan Medical School
Namgyu Lee: University of Massachusetts Chan Medical School
Tenzin Tseyang: University of Massachusetts Chan Medical School
Olga Ponomarova: University of Massachusetts Chan Medical School
Hira Lal Goel: University of Massachusetts Chan Medical School
Meghan Spears: University of Massachusetts Chan Medical School
Rui Li: University of Massachusetts Chan Medical School
Lihua Julie Zhu: University of Massachusetts Chan Medical School
Christopher Ashwood: Beth Israel Deaconess Medical Center
Karl Simin: University of Massachusetts Chan Medical School
Cholsoon Jang: University of California, Irvine
Arthur M. Mercurio: University of Massachusetts Chan Medical School
Albertha J. M. Walhout: University of Massachusetts Chan Medical School
Jessica B. Spinelli: University of Massachusetts Chan Medical School
Dohoon Kim: University of Massachusetts Chan Medical School

Nature, 2023, vol. 623, issue 7987, 625-632

Abstract: Abstract Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge1. Here we report a therapeutic vulnerability in a sugar nucleotide biosynthetic pathway that can be exploited in cancer cells with only a limited impact on normal cells. A systematic examination of conditionally essential metabolic enzymes revealed that UXS1, a Golgi enzyme that converts one sugar nucleotide (UDP-glucuronic acid, UDPGA) to another (UDP-xylose), is essential only in cells that express high levels of the enzyme immediately upstream of it, UGDH. This conditional relationship exists because UXS1 is required to prevent excess accumulation of UDPGA, which is produced by UGDH. UXS1 not only clears away UDPGA but also limits its production through negative feedback on UGDH. Excess UDPGA disrupts Golgi morphology and function, which impedes the trafficking of surface receptors such as EGFR to the plasma membrane and diminishes the signalling capacity of cells. UGDH expression is elevated in several cancers, including lung adenocarcinoma, and is further enhanced during chemoresistant selection. As a result, these cancer cells are selectively dependent on UXS1 for UDPGA detoxification, revealing a potential weakness in tumours with high levels of UGDH.

Date: 2023
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DOI: 10.1038/s41586-023-06676-3

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