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

TitleGenome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC
Authors
KeywordsCancer
Cancer metabolism
Cancer therapy
Gastrointestinal cancer
Hepatocellular carcinoma
Issue Date2019
PublisherNature Research (part of Springer Nature): Fully open access journals. The Journal's web site is located at http://www.nature.com/ncomms/index.html
Citation
Nature Communications, 2019, v. 10 n. 1, p. article no. 4681 How to Cite?
AbstractSorafenib 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.
Persistent Identifierhttp://hdl.handle.net/10722/281910
ISSN
2023 Impact Factor: 14.7
2023 SCImago Journal Rankings: 4.887
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWei, L-
dc.contributor.authorLEE, D-
dc.contributor.authorLaw, C-T-
dc.contributor.authorZhang, MS-
dc.contributor.authorSHEN, J-
dc.contributor.authorChin, DW-C-
dc.contributor.authorZhang, A-
dc.contributor.authorTsang, FH-C-
dc.contributor.authorWONG, CL-S-
dc.contributor.authorNg, IO-L-
dc.contributor.authorWong, CC-L-
dc.contributor.authorWong, C-M-
dc.date.accessioned2020-04-03T07:23:31Z-
dc.date.available2020-04-03T07:23:31Z-
dc.date.issued2019-
dc.identifier.citationNature Communications, 2019, v. 10 n. 1, p. article no. 4681-
dc.identifier.issn2041-1723-
dc.identifier.urihttp://hdl.handle.net/10722/281910-
dc.description.abstractSorafenib 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.-
dc.languageeng-
dc.publisherNature Research (part of Springer Nature): Fully open access journals. The Journal's web site is located at http://www.nature.com/ncomms/index.html-
dc.relation.ispartofNature Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCancer-
dc.subjectCancer metabolism-
dc.subjectCancer therapy-
dc.subjectGastrointestinal cancer-
dc.subjectHepatocellular carcinoma-
dc.titleGenome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC-
dc.typeArticle-
dc.identifier.emailLaw, C-T: ctlawaa@connect.hku.hk-
dc.identifier.emailZhang, MS: mistyzs@hku.hk-
dc.identifier.emailNg, IO-L: iolng@hku.hk-
dc.identifier.emailWong, CC-L: carmencl@pathology.hku.hk-
dc.identifier.emailWong, C-M: jcmwong@hku.hk-
dc.identifier.authorityNg, IO-L=rp00335-
dc.identifier.authorityWong, CC-L=rp01602-
dc.identifier.authorityWong, C-M=rp00231-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41467-019-12606-7-
dc.identifier.pmid31615983-
dc.identifier.pmcidPMC6794322-
dc.identifier.scopuseid_2-s2.0-85073465574-
dc.identifier.hkuros309595-
dc.identifier.volume10-
dc.identifier.issue1-
dc.identifier.spagearticle no. 4681-
dc.identifier.epagearticle no. 4681-
dc.identifier.isiWOS:000490117300004-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl2041-1723-

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