The mTOR kinase inhibitor everolimus synergistically enhances the anti‐tumor effect of the Janus kinase 1 (JAK1) inhibitor AZD4205 on Peripheral T cell lymphoma

Abstract

Introduction: Peripheral T-cell lymphoma (PTCL) constitute a heterogenous group of non-Hodgkin lymphomas, which is distinguished by their aggressive courses and poor clinical outcomes. Multiple researches have indicated that the JAK/STAT pathway acts as an important role in the mechanism of TCL pathogenesis. Preliminary results from related clinical studies showed that JAK inhibitors have a high remission rate and durable response in PTCL patients. AZD4205 is a potent JAK1-selective inhibitor currently evaluated in phase II clinical studies in PTCLs, which could reduce the side effects caused by JAK2 blockade by selectively targeting JAK1. Therefore, the aim of this study is to explore the efficacy and appropriate combination regimen of the novel JAK1 inhibitor AZD4205 in PTCL and to decipher the underlying anti-tumor mechanism. Methods: We analyzed the expression of JAK/STAT pathway in PTCL tissues via bioinformatics analysis and IHC. In vitro cell viability was assessed by using Cell Titer-Glo Luminescent assay. Induction of cell apoptosis was measured by flow cytometry. Western blot was utilized to identify the influence of AZD4205 on the intracellular relevant signaling pathways. The effects of AZD4205 on the transcriptome of PTCL cells were analyzed via transcriptome sequencing technology. High-throughput compounds screening was applied to explore potential combination therapeutic targets of AZD4205. Tumor-bearing mouse models were established to validate the efficacy and safety of AZD4205 and the combination regimen. Results: High expression of phosphorylated JAK1 in PTCL tissues are potential poor prognostic factors. The JAK1 inhibitor AZD4205 inhibited the proliferation of PTCL cells and down-regulated the activation of JAK/STAT signaling pathway. In addition, AZD4205 induced apoptosis in PTCL cells, and showed anti-tumor effects in vivo. However, AZD4205 also induced adverse effects of hepatic impairment and dyslipidemia in vivo. Transcriptome sequencing analysis revealed that AZD4205 treatment upregulated the expression of mTOR pathway-related genes. Moreover, high-throughput screening assay showed that the mTOR inhibitor everolimus significantly enhanced the inhibitory efficacy of AZD4205. We further confirmed that AZD4205 combined with the mTOR inhibitor everolimus exerted synergistic anti-PTCL efficacy both in vitro and in vivo, and the combination regimen significantly reduced AZD4205-induced adverse effects. The RNA-seq results suggested that the combination treatment affected the cholesterol homeostasis pathway and a further validation of the combined anti-PTCL effect of mevastatin and AZD4205 was confirmed in mouse models. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.