Enhanced Anti-Pediatric Sarcomas Effect of Everolimus with Secukinumab by Targeting IL-17A.

In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. Additionally, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. Immunohistochemistry and western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared to cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an up-regulation in the level of interleukin (IL)-17A in sarcoma cells. Notably, when secukinumab, a monoclonal antibody of IL-17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an anti-pediatric sarcomas effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL-17A, which promotes tumor cell survival and counteracts its anti-pediatric sarcomas effect. The combination of secukinumab effectively eliminates the effects of IL-17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.

Citation

Dan Huang, Zhipeng Wu, Zhengyi Wu, Nuoya Li, Liang Hao, Kuangfan Li, Junquan Zeng, Bingbing Qiu, Shouhua Zhang, Jinlong Yan. Enhanced Anti-Pediatric Sarcomas Effect of Everolimus with Secukinumab by Targeting IL-17A. Molecular cancer therapeutics. 2024 Jan 31

PMID: 38295302

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