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Genome-Wide CRISPR/Cas9 Library Screening Identified that DUSP4 Deficiency Induces Lenvatinib Resistance in Hepatocellular Carcinoma. | LitMetric

AI Article Synopsis

  • - Lenvatinib is used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but drug resistance limits its effectiveness, with the mechanisms behind this resistance not fully understood.
  • - Researchers used CRISPR/Cas9 screening and other assays to identify six key genes related to Lenvatinib resistance, particularly focusing on DUSP4, which is linked to increased cancer cell survival and proliferation during treatment.
  • - DUSP4 deficiency enhances drug resistance through activation of the MAPK/ERK signaling pathway, and combining Lenvatinib with MEK inhibitors shows potential to improve treatment outcomes for patients with HCC.

Article Abstract

Lenvatinib is in a first-line therapy for advanced hepatocellular carcinoma (HCC). However, drug resistance is one of the principal obstacles for treatment failure. The molecular mechanism of Lenvatinib resistance has not been well investigated. A genome-wide CRISPR/Cas9 knockout screening system was established and bioinformatic analysis was used to identify critical genes associated with Lenvatinib resistance. Cell proliferation assays, colony formation assays and cell migration assays were performed to investigate the effect of drug resistance associated genes, particularly DUSP4, on cancer cell malignant behavior during Lenvatinib treatment. experiments were conducted by using a xenograft mouse model. We identified six genes that were associated with Lenvatinib resistance in HCC, including DUSP4, CCBL1, DHDH, CNTN2, NOS3 and TNF. DUSP4 was found to be significantly decreased at the mRNA and protein levels in Lenvatinib resistant HCC cells. DUSP4 knockout enhanced HCC cell survival, cell proliferation and migration during Lenvatinib treatment and , accompanied by regulation of p-ERK and p-MEK levels. This finding implied that DUSP4 deficiency induced Lenvatinib resistance. Interestingly, DUSP4 deficiency induced Lenvatinib resistance was abrogated by the MEK inhibitor Selumetinib, implying that MEK phosphorylation and DUSP4-inhibition dependent ERK activation were required for drug resistance. Finally, we found that DUSP4 deficiency was associated with HCC prognosis and response to Lenvatinib based on clinical data. DUSP4 deficiency mediates Lenvatinib resistance by activating MAPK/ERK signaling and combination therapy using Lenvatinib and MEK inhibitors may be a promising therapeutic strategy for overcoming Lenvatinib resistance.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295068PMC
http://dx.doi.org/10.7150/ijbs.69969DOI Listing

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  • - Lenvatinib is a key treatment for hepatocellular carcinoma (HCC) that works by blocking critical growth factor receptors, which helps reduce tumor growth and improves immune response.
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