Goad Dakota W, Bressy Christian, Holbrook Molly C, Grdzelishvili Valery Z
Department of Biological Sciences, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA.
School of Data Science, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
Mol Ther Oncolytics. 2021 Dec 1;24:59-76. doi: 10.1016/j.omto.2021.11.019. eCollection 2022 Mar 17.
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.
水泡性口炎病毒（VSV）是一种有前景的溶瘤病毒（OV），可用于对抗包括胰腺导管腺癌（PDAC）在内的不同恶性肿瘤。我们之前的研究表明，基于VSV的溶瘤病毒对大多数测试的人类PDAC细胞系有效。然而，一些PDAC细胞系对VSV具有抗性。PDAC是人类最致命的恶性肿瘤类型之一，部分原因是其内在的或获得性的化疗耐药性。在此，我们研究了获得性化疗耐药性如何影响基于VSV的溶瘤病毒疗法的疗效。我们采用实验进化方法，生成了对吉西他滨耐药性增强的PDAC细胞系，并检测了它们对溶瘤病毒疗法的反应性。我们发现，吉西他滨耐药的PDAC细胞对VSV的耐药性更强。这种交叉耐药性与一组干扰素刺激基因的上调水平相关，类似于干扰素相关DNA损伤抗性特征（IRDS），这通常与癌细胞对化疗和/或放疗的耐药性有关。对十种不同的PDAC细胞系进行分析表明，对VSV耐药性最强的四种PDAC细胞系对吉西他滨也具有高度耐药性，并且在我们之前的报告中它们均表现出类似IRDS的表达。我们的研究强调了两种不同疗法之间可能存在的相互作用，在未来制定合理的治疗方案时应予以考虑。
