Oncolytic virus synergizes with Smac mimetic compounds to induce rhabdomyosarcoma cell death in a syngeneic murine model

Janelle Chabot,Martin Holcik,Robert G Korneluk,Mame D Faye,Shawn T Beug,Christine C Dobson,David F Stojdl,Martin St-Jean,Eric C Lacasse,Danielle E Walker,Thet Naing

doi:10.18632/oncotarget.13849

Janelle Chabot, Martin Holcik + Show 9 more

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https://doi.org/10.18632/oncotarget.13849

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Abstract

Rhabdomyosarcoma (RMS), a neoplasm characterized by undifferentiated myoblasts, is the most common soft tissue tumour in children. Therapeutic resistance is common in RMS and is often caused by acquired defects in the cellular apoptotic program. Smac mimetic compounds (SMCs) are a novel class of inhibitor of apoptosis (IAP) antagonists that are currently under clinical development as cancer therapeutics. We previously reported that cIAP1 is overexpressed in human primary RMS tumours and in patient-derived RMS cell lines where it drives resistance to apoptosis. In this study, we investigated whether inflammatory cytokine production triggered by activators of innate immunity synergizes with LCL161 to induce bystander killing of RMS cells in vitro and in vivo. Indeed, we show that innate immune stimuli (oncolytic virus (VSVΔ51-GFP), interferon γ (IFNγ), and tumour necrosis factor-like weak inducer of apoptosis (TWEAK)) combine with SMCs in vitro to reduce cell viability in the Kym-1 RMS cancer cell line. Other human RMS cell lines (RH36, RH41, RD, RH18, RH28, and RH30) and the murine RMS cell line 76-9 are resistant to treatment with LCL161 alone or in combination with immune stimulants in in vitro cell viability assays. In contrast, we report that the combination of LCL161 and VSVΔ51-GFP reduces tumour volume and prolongs survival in a 76-9 syngeneic murine model. Our results support further exploration of the combined use of IAP antagonists and innate immune stimuli as a therapeutic approach for RMS cancers.

Highlights

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, representing 3-4% of all childhood cancers [1]
When Kym1 cells were treated with concentrations of ≤100 nM of LCL161 for 24 h, cell viability was reduced to levels that were indistinguishable from blanks
To determine whether sensitivity of RMS cells to LCL161 was related to cIAP1 protein expression, western blotting was used to assess www.impactjournals.com/oncotarget cIAP1 expression in cells treated with vehicle (DMSO) or LCL161 for 24 h (Figure 1B)

Summary

Introduction

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, representing 3-4% of all childhood cancers [1]. Impaired apoptosis plays a key role in the pathogenesis of RMS www.impactjournals.com/oncotarget and contributes to chemotherapeutic resistance by two main mechanisms: 1) preventing cells from responding to pro-apoptotic signals and 2) via the upregulation of anti-apoptotic proteins [6]. The eight human IAP members are defined by the presence of a canonical zinc-finger BIR domain and a carboxy-terminal RING finger domain with E3 ubiquitin ligase activity [8]. Among this family of proteins, the structurally similar cellular IAP 1 (cIAP1) and cIAP2 proteins are key regulators of tumour necrosis factor-α (TNFα) and related cytokine members signaling through regulation of the classical and alternative nuclear factorκB signaling pathways [8, 9]. Tumour cell lines that can produce endogenous TNFα (~5-10% of cancer cell lines) are sensitive to SMCs alone, but pro-death cytokine ligands are often required for maximal SMC efficacy [8, 11, 12]

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