Pacritinib 是一种口服药物，可抑制多种激酶，包括 JAK2、FLT3、IRAK 和 STAT3。它最近被批准用于治疗血小板减少症和骨髓纤维化患者。目前的研究正在探索 pacritinib 在治疗其他类型癌症（如白血病、乳腺癌和前列腺癌）中的潜在用途。我们的研究旨在调查单独使用 pacritinib 及其与标准护理联合治疗肾细胞癌 (RCC) 的效果。我们发现 pacritinib 剂量依赖性地降低 RCC 细胞的活力，IC50 在纳摩尔或低微摩尔浓度范围内。 Pacritinib 抑制细胞增殖、减少集落形成并增加细胞凋亡。有趣的是，在一组 RCC 细胞系中，pacritinib 与替西罗莫司和舒尼替尼联合使用时表现出协同作用，但与阿霉素联合使用时表现出拮抗作用。我们还证实，pacritinib 与替西罗莫司和舒尼替尼的组合在 RCC 小鼠模型中产生协同作用，在整个治疗期间完全抑制肿瘤生长。机制研究表明，抑制 JAK2（而非 IRAK）是 pacritinib 抗 RCC 活性的主要贡献者。我们的研究首次证明 pacritinib 作为 RCC 的治疗选择具有前景，并强调了针对 RCC 中 JAK2/STAT 信号通路的治疗潜力。

Pacritinib is an oral medication that inhibits several kinases including JAK2, FLT3, IRAK and STAT3. It has been recently approved to treat patients with thrombocytopenia and myelofibrosis. Studies are currently exploring the potential use of pacritinib in treating other types of cancer such as leukaemia, breast cancer and prostate cancer. Our study aimed to investigate the effects of pacritinib alone and its combination with standard of care in renal cell carcinoma (RCC). We showed that pacritinib dose-dependently decreased viability of RCC cells, with IC50 at nanomolar or low micromolar concentration rage. Pacritinib inhibited cell proliferation, decreased colony formation, and increased apoptosis. Interestingly, pacritinib exhibited synergistic effects when combined with temsirolimus and sunitinib, but antagonistic effects when combined with doxorubicin, in a panel of RCC cell lines. We also confirmed that the combination of pacritinib with temsirolimus and sunitinib resulted in synergistic effects in RCC mouse models, with complete inhibition of tumour growth throughout the treatment period. Mechanistic studies indicated that the inhibition of JAK2, but not IRAK, was the main contributor to the anti-RCC activity of pacritinib. Our study is the first to demonstrate that pacritinib shows promise as a treatment option for RCC and underscores the therapeutic potential of targeting the JAK2/STAT signalling pathway in RCC.