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

Author

Listed:
  • Lai Wei

    (The University of Hong Kong
    The University of Hong Kong)

  • Derek Lee

    (The University of Hong Kong
    The University of Hong Kong)

  • Cheuk-Ting Law

    (The University of Hong Kong
    The University of Hong Kong)

  • Misty Shuo Zhang

    (The University of Hong Kong
    The University of Hong Kong)

  • Jialing Shen

    (The University of Hong Kong
    The University of Hong Kong)

  • Don Wai-Ching Chin

    (The University of Hong Kong
    The University of Hong Kong)

  • Allen Zhang

    (The University of Hong Kong
    The University of Hong Kong)

  • Felice Ho-Ching Tsang

    (The University of Hong Kong
    The University of Hong Kong)

  • Ceci Lok-Sze Wong

    (The University of Hong Kong
    The University of Hong Kong)

  • Irene Oi-Lin Ng

    (The University of Hong Kong
    The University of Hong Kong)

  • Carmen Chak-Lui Wong

    (The University of Hong Kong
    The University of Hong Kong)

  • Chun-Ming Wong

    (The University of Hong Kong
    The University of Hong Kong)

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.

Suggested Citation

  • 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-Mi, 2019. "Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12606-7
    DOI: 10.1038/s41467-019-12606-7
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    Cited by:

    1. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Bei Wang & Arabella H. Wan & Yu Xu & Ruo-Xin Zhang & Ben-Chi Zhao & Xin-Yuan Zhao & Yan-Chuan Shi & Xiaolei Zhang & Yongbo Xue & Yong Luo & Yinyue Deng & G. Gregory Neely & Guohui Wan & Qiao-Ping Wang, 2023. "Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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