Department of Biology, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States.
School of Medicine, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States.
Cancer Treat Res Commun. 2021;27:100340. doi: 10.1016/j.ctarc.2021.100340. Epub 2021 Feb 17.
Cancer cells almost universally harbor constitutively active Phosphatidylinositol-3 Kinase (PI3K) Pathway activity via mutation of key signaling components and/or epigenetic mechanisms. Scores of PI3K Pathway inhibitors are currently under investigation as putative chemotherapeutics. However, feedback and stem cell mechanisms induced by PI3K Pathway inhibition can lead to reduced treatment efficacy. To address therapeutic barriers, we examined whether JAKi would reduce stem gene expression in a setting of PI3K Pathway inhibition in order to improve treatment efficacy. We targeted the PI3K Pathway with NVP-BEZ235 (dual PI3K and mTOR inhibitor) in combination with the Janus Kinase inhibitor JAKi in glioblastoma (GBM) and basal-like breast cancer (BBC) cell lines. We examined growth, gene expression, and apoptosis in cells treated with NVP-BEZ235 and/or JAKi. Growth and recovery assays showed no significant impact of dual treatment with NVP-BEZ235/JAKi compared to NVP-BEZ235 treatment alone. Gene expression and flow cytometry revealed that single and dual treatments induced apoptosis. Stem gene expression was retained in dual NVP-BEZ235/JAKi treatment samples. Future in vivo studies may give further insight into the impact of combined NVP-BEZ235/JAKi treatment in GBM and BBC.
癌细胞普遍通过关键信号成分的突变和/或表观遗传机制，保持磷脂酰肌醇-3 激酶（PI3K）通路的持续激活。目前有大量的 PI3K 通路抑制剂被作为潜在的化疗药物进行研究。然而，PI3K 通路抑制所诱导的反馈和干细胞机制可能导致治疗效果降低。为了解决治疗障碍，我们研究了在 PI3K 通路抑制的情况下，JAKi 是否会降低干细胞基因表达，从而提高治疗效果。我们用 NVP-BEZ235（双重 PI3K 和 mTOR 抑制剂）靶向 PI3K 通路，并用 Janus 激酶抑制剂 JAKi 联合治疗胶质母细胞瘤（GBM）和基底样乳腺癌（BBC）细胞系。我们检测了用 NVP-BEZ235 和/或 JAKi 处理的细胞的生长、基因表达和凋亡情况。生长和恢复实验表明，与单独用 NVP-BEZ235 治疗相比，用 NVP-BEZ235/JAKi 双重治疗并没有显著的影响。基因表达和流式细胞术显示，单一和双重治疗都能诱导细胞凋亡。在双重 NVP-BEZ235/JAKi 处理的样本中，干细胞基因表达仍然存在。未来的体内研究可能会进一步深入了解 NVP-BEZ235/JAKi 联合治疗在 GBM 和 BBC 中的作用。
