Overcoming cancer cell resistance to VSV oncolysis with JAK1/2 inhibitors

Abstract

Oncolytic vesicular stomatitis virus (VSV) has potent antitumor activity but some cancer cells are resistant to VSV killing, either constitutively or due to type I interferon (IFN) inducing an antiviral state in the cells. Here, we evaluated VSV oncolysis of a panel of human head and neck cancer cells and showed that VSV resistance in SCC25 and SCC15 cells could be reversed with Janus kinase (JAK) 1/2 inhibitors (JAK inhibitor I and ruxolitinib). Pre-treatment of cells with JAK1/2 inhibitors before or in conjunction with VSV enhanced viral infection, spread and progeny yield (100- to 1000-fold increase). In contrast, inhibitors of histone deacetylase (LBH589), phosphatidylinositol 3-kinase (GDC-0941, LY294002), mammalian target of rapamycin (rapamycin) or signal transducer and activator of transcription 3 (STAT3 inhibitor VII) were ineffective. Compared with VSV-sensitive SW579 cells, IFNα/β responsive antiviral genes (IRF-9, IRF-7, OAS1 but not MxA) are constitutively expressed in SCC25 cells. Pretreatment with JAK inhibitors reduced mRNA levels of these genes, increasing VSV expression in the cells. Interestingly, 1 h of drug exposure was sufficient to reverse SCC25 resistance to VSV and was still effective if virus was added 24 h later. Overall, we show here that JAK inhibitor I and ruxolitinib (Jakafi) can reverse resistance to VSV, supporting the rationale to incorporate JAK1/2 inhibitors in future VSV virotherapy trials.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…Similarly, several ISGs (IRF-9, IRF-7 and OAS) were found to be constitutively expressed in VSV-resistant human head and neck cancer cells. Combining JAK Inhibitor I or ruxolitinib with VSV or VSV-DM51 enhanced viral infection, spread and progeny yield in a panel of human head and neck cancer cells [68]. Recently, for the first time, an in vivo enhancement of oncolytic VSV-GP treatment by ruxolitinib was reported, both in subcutaneous as well as in orthotopic xenograft mouse ovarian cancer models [69].…”

Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

“…In one study, VSV-resistant prostate tumor cells became sensitive to infection and cytolysis in vitro and in vivo after treatment with triptolide, a drug that was shown to block type I IFN signaling at the transcriptional level (53). In another study, treatment with specific JAK1/2 inhibitors increased the susceptibility of head and neck cancer cells to VSVinduced oncolysis (33). The current study provides a clinically relevant example of differential IFN-induced bioactivity and illustrates the need for further study on the contribution of individual IFN subtypes to tumor cell resistance to VSV and other oncolytic viruses.…”

“…Cancer cell resistance to VSV and other oncolytic viruses often is due to partial or full retention of type I IFN responsiveness and/or to constitutive expression of IFN-stimulated antiviral genes (6,13,(29)(30)(31)(32)(33)(34). The human type I IFN family includes 12 subtypes of IFN-␣ and one subtype of IFN-␤, all of which share significant amino acid homology (35).…”

Faster Replication and Higher Expression Levels of Viral Glycoproteins Give the Vesicular Stomatitis Virus/Measles Virus Hybrid VSV-FH a Growth Advantage over Measles Virus

“…There is an ongoing search for clinically viable drugs, such as Jak1/2 inhibitors (e.g., ruxolitinib), that could be combined with VSV virotherapy such that cellular antiviral resistance to VSV could be reversed (20).…”

“…A semiquantitative PCR (26 cycles, optimized to stop the PCR within the logarithmic phase) was done using Taq DNA polymerase (Life Technologies, Carlsbad, CA) according to the manufacturer's protocol. The primers used have been previously described (19,20).…”