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Genome-wide CRISPR/Cas9 Library Screening Identified PHGDH as a Critical Driver for Sorafenib Resistance in HCC

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, Chun-Ming Wong

Nat Commun. 2019 Oct 15;10(1):4681.

PMID: 31615983

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1916571908	NCT-503		1916571-90-8	Price

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