A genome-wide CRISPR activation screen reveals Hexokinase 1 as a critical factor in promoting resistance to multi-kinase inhibitors in hepatocellular carcinoma cells.
Animals
Antineoplastic Agents
/ therapeutic use
Carcinoma, Hepatocellular
/ drug therapy
Cell Line, Tumor
Cells, Cultured
Drug Resistance, Neoplasm
Hexokinase
/ genetics
Humans
Liver Neoplasms
/ drug therapy
Male
Mice
Mice, Inbred NOD
Mutation
Protein Kinase Inhibitors
/ therapeutic use
Up-Regulation
CRISPR activation
hepatocellular carcinoma
tyrosine-kinase inhibitors
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
27
12
2021
received:
22
09
2021
accepted:
20
01
2022
entrez:
11
2
2022
pubmed:
12
2
2022
medline:
5
3
2022
Statut:
ppublish
Résumé
Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage and is, therefore, treated with systemic drugs, such as tyrosine-kinase inhibitors (TKIs). These drugs, however, offer only modest survival benefits due to the rapid development of drug resistance. To identify genes implicated in TKI resistance, a cluster of regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 activation screen was performed in hepatoma cells treated with regorafenib, a TKI used as second-line therapy for advanced HCC. The screen results show that Hexokinase 1 (HK1), catalyzing the first step in glucose metabolism, is a top candidate for conferring TKI resistance. Compatible with this, HK1 was upregulated in regorafenib-resistant cells. Using several experimental approaches, both in vitro and in vivo, we show that TKI resistance correlates with HK1 expression. Furthermore, an HK inhibitor resensitized resistant cells to TKI treatment. Together, our data indicate that HK1 may function as a critical factor modulating TKI resistance in hepatoma cells and, therefore, may serve as a biomarker for treatment success.
Identifiants
pubmed: 35147243
doi: 10.1096/fj.202101507RR
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
HK1 protein, mouse
EC 2.7.1.1
Hexokinase
EC 2.7.1.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e22191Informations de copyright
© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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