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Updated: Mar 11, 2026
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
Gene expression profiling of hematologic malignant cell lines resistant to oncolytic virus treatment
Nam Hee Lee1,2, Mikyung Kim1, Sung Yong Oh3
1SillaJen, Inc., Busan, Korea.
Abstract:
Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.
Insights
Pexa-Vec (pexastimogene devacirpvec) shows promise in oncolytic virotherapy, but lymphoid cancers resist its effects. Identifying specific gene expression patterns in resistant cells offers potential strategies to overcome this challenge.
Area of Science:
- Oncolytic virotherapy
- Cancer genomics
- Gene expression analysis
Background:
- Pexa-Vec (pexastimogene devacirpvec; JX-594) is an oncolytic virus with therapeutic potential.
- Understanding resistance mechanisms to Pexa-Vec is crucial for optimizing its clinical use.
Purpose of the Study:
- To investigate the gene expression patterns in hematologic malignant cells sensitive and resistant to Pexa-Vec.
- To identify potential molecular targets for overcoming Pexa-Vec resistance.
Main Methods:
- Hematologic cell lines (myeloid and lymphoid) were treated with Pexa-Vec.
- Gene expression profiling was performed using microarray analysis.
- Differential gene expression was analyzed between sensitive and resistant cell lines.
Main Results:
- Pexa-Vec exhibited dose-dependent cytotoxicity in myeloid cell lines.
- Lymphoid cancer cell lines showed resistance to Pexa-Vec, with distinct gene expression profiles.
- Specific genes, including LEF1, STAMBPL1, SLFN11, PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, and CD1d, were identified as correlating with viral replication or resistance.
Conclusions:
- Lymphoid malignant cells are inherently resistant to Pexa-Vec due to specific gene up-regulations.
- Identified genes represent potential targets to enhance Pexa-Vec efficacy.
- Molecular assays could aid in patient selection for Pexa-Vec clinical trials.
