A genome-wide CRISPR activation screen reveals Hexokinase 1 as a critical factor in promoting resistance to multi-kinase inhibitors in hepatocellular carcinoma cells

Summer Sofer, Kevin Lamkiewicz, Shir Armoza Eilat, Shirly Partouche, Manja Marz, Neta Moskovits, Salomon M. Stemmer, Amir Shlomai, Ella H. Sklan

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere22191
JournalFASEB Journal
Volume36
Issue number3
DOIs
StatePublished - Mar 2022

Keywords

  • CRISPR activation
  • hepatocellular carcinoma
  • tyrosine-kinase inhibitors

Fingerprint

Dive into the research topics of 'A genome-wide CRISPR activation screen reveals Hexokinase 1 as a critical factor in promoting resistance to multi-kinase inhibitors in hepatocellular carcinoma cells'. Together they form a unique fingerprint.

Cite this