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

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Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC.
Nature Communications ( IF 14.7 ) Pub Date : 2019-10-15 , DOI: 10.1038/s41467-019-12606-7
Lai Wei _{1,

2} , Derek Lee _{1,

2} , Cheuk-Ting Law _{1,

2} , Misty Shuo Zhang _{1,

2} , Jialing Shen _{1,

2} , Don Wai-Ching Chin _{1,

2} , Allen Zhang _{1,

2} , Felice Ho-Ching Tsang _{1,

2} , Ceci Lok-Sze Wong _{1,

2} , Irene Oi-Lin Ng _{1,

2} , Carmen Chak-Lui Wong _{1,

2} , Chun-Ming Wong _{1,

2}

Affiliation

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.

中文翻译：

全基因组CRISPR / Cas9文库筛选确定PHGDH是肝癌中索拉非尼耐药性的关键驱动因素。

索拉非尼是晚期肝细胞癌（HCC）的标准治疗方法。然而，耐药性的发展是普遍的。通过使用全基因组的CRISPR / Cas9文库筛选，我们确定磷酸甘油酸脱氢酶（PHGDH）是丝氨酸合成途径（SSP）中的第一个定型酶，是索拉非尼耐药的关键驱动因素。索拉非尼治疗通过诱导PHGDH表达来激活SSP。使用RNAi敲低和CRISPR / Cas9敲除模型，我们显示PHGDH的失活使SSP麻痹，并减少了αKG，丝氨酸和NADPH的产生。同时，索拉非尼治疗后，PHGDH的失活会升高ROS水平并诱导HCC凋亡。更令人吃惊的是，PHGDH抑制剂NCT-503的治疗与索拉非尼协同作用，可消除体内HCC的生长。在其他FDA批准的酪氨酸激酶抑制剂（TKI）中也获得了类似的发现，包括Regorafenib或Lenvatinib。总之，我们的结果表明，靶向PHGDH是克服HCC中TKI耐药性的有效方法。

更新日期：2019-10-16

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