Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus

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Grdzelishvili, V., Goad, D., Bressy, C., & Holbrook, M. (2022). Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus. Molecular Therapy Oncolytics. https://doi.org/doi:10.1016/j.omto.2021.11.019
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Description

Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV) against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies have demonstrated that VSV-based OVs are effective against the majority of tested human PDAC cell lines. However, some PDAC cell lines are resistant to VSV. PDAC is one of the deadliest types of human malignancies in part due to intrinsic or acquired chemoresistance. Here, we investigated how acquired chemoresistance impacts the efficacy of VSV-based OV therapy. Using an experimental evolution approach, we generated PDAC cell lines with increased resistance to gemcitabine and examined their responsiveness to oncolytic virotherapy. We found that gemcitabine-resistant PDAC cells become more resistant to VSV. The cross-resistance correlated with upregulated levels of a subset of interferon-stimulated genes, resembling the interferon-related DNA damage resistance signature (IRDS), often associated with resistance of cancer cells to chemotherapy and/or radiation therapy. Analysis of ten different PDAC cell lines showed that four PDAC cell lines most resistant to VSV were also highly resistant to gemcitabine, and they all displayed IRDS-like expression in our previous reports. Our study highlights a possible interaction between two different therapies that should be considered in the future for the development of rational treatment regimens.

Details
Title

Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus

Author(s)

Grdzelishvili, Valery
Goad, Dakota
Bressy, Christian
Holbrook, Molly

UNC Charlotte Affiliate Type

Faculty

Extent

1 online resource

Date Published

2022

Material Type

Journal article

Genre

articles

Resource Type

text

Abstract

Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV) against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies have demonstrated that VSV-based OVs are effective against the majority of tested human PDAC cell lines. However, some PDAC cell lines are resistant to VSV. PDAC is one of the deadliest types of human malignancies in part due to intrinsic or acquired chemoresistance. Here, we investigated how acquired chemoresistance impacts the efficacy of VSV-based OV therapy. Using an experimental evolution approach, we generated PDAC cell lines with increased resistance to gemcitabine and examined their responsiveness to oncolytic virotherapy. We found that gemcitabine-resistant PDAC cells become more resistant to VSV. The cross-resistance correlated with upregulated levels of a subset of interferon-stimulated genes, resembling the interferon-related DNA damage resistance signature (IRDS), often associated with resistance of cancer cells to chemotherapy and/or radiation therapy. Analysis of ten different PDAC cell lines showed that four PDAC cell lines most resistant to VSV were also highly resistant to gemcitabine, and they all displayed IRDS-like expression in our previous reports. Our study highlights a possible interaction between two different therapies that should be considered in the future for the development of rational treatment regimens.

Subjects--Topics

Vesicular stomatitis
Cancer
Viruses

Is Part Of

Molecular therapy oncolytics

Volume

Vol. 24

Beginning Page Number

59

Ending Page Number

76

Language

English

Published Version (Please cite this version)

doi:10.1016/j.omto.2021.11.019

Publisher's Version

https://www.cell.com/action/showPdf?pii=S2372-7705%2821%2900168-6

Permalink

http://hdl.handle.net/20.500.13093/work:252

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