Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC

Lai Wei, Derek Lee, Cheuk-Ting Law, Misty Shuo Zhang, Jialing Shen, Don Wai-Ching Chin, Allen Zhang, Felice Ho-Ching Tsang, Ceci Lok-Sze Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong () and Chun-Ming Wong ()
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Lai Wei: The University of Hong Kong
Derek Lee: The University of Hong Kong
Cheuk-Ting Law: The University of Hong Kong
Misty Shuo Zhang: The University of Hong Kong
Jialing Shen: The University of Hong Kong
Don Wai-Ching Chin: The University of Hong Kong
Allen Zhang: The University of Hong Kong
Felice Ho-Ching Tsang: The University of Hong Kong
Ceci Lok-Sze Wong: The University of Hong Kong
Irene Oi-Lin Ng: The University of Hong Kong
Carmen Chak-Lui Wong: The University of Hong Kong
Chun-Ming Wong: The University of Hong Kong

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. Sorafenib treatment activates SSP by inducing PHGDH expression. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that inactivation of PHGDH paralyzes the SSP and reduce the production of αKG, serine, and NADPH. Concomitantly, inactivation of PHGDH elevates ROS level and induces HCC apoptosis upon Sorafenib treatment. More strikingly, treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC growth in vivo. Similar findings are also obtained in other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC.

Date: 2019
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DOI: 10.1038/s41467-019-12606-7

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