Tan Jiaqi, Bao Ziyi, Qin Kai, Zhu Liujing, Zheng Changwu, Jin Jiabin, Zhang Li, Xu Hongxi
School of Pharmacy Shanghai University of Traditional Chinese Medicine Shanghai China.
Department of General Surgery Pancreatic Disease Center Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China.
MedComm (2020). 2025 Jul 1;6(7):e70250. doi: 10.1002/mco2.70250. eCollection 2025 Jul.
Mutations in mitogen-activated protein kinase kinase (MEK) are prevalent in pancreatic ductal adenocarcinoma (PDAC), but many MEK inhibitors inadvertently activate protein kinase B (AKT). We propose a promising PDAC treatment strategy by combining the MEK inhibitor trametinib with neobractatin (NBT), a natural compound from . Our results demonstrated that this combination significantly impeded cell growth by inducing gasdermin E (GSDME)-mediated pyroptosis and apoptosis. GSDME, overexpressed in PDAC tissues and correlated with histological differentiation, underscores the role of pyroptosis in PDAC. RNA-seq results indicated that the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was the primary target of the combination treatment. Mechanistic studies revealed the combination effectively reduced both total and phosphorylated AKT levels, thereby inhibiting protein kinase B/IκB kinase (AKT/IKK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathways. Additionally, the combination disrupted mTOR complex 2 (mTORC2), preventing the trametinib-induced AKT activation. MicroRNA sequencing analysis indicated that the combination reduced AKT levels by upregulated miR-149-5p. Further research demonstrated that the combination increased intracellular reactive oxygen species (ROS), while N-acetylcysteine (NAC, a ROS scavenger) reversed the cell growth inhibition and AKT suppression. In vivo, the combination significantly inhibited tumor growth by inducing pyroptosis and apoptosis, outperforming gemcitabine. Our findings provide novel insights into the potential of combining NBT and trametinib to induce pyroptosis and apoptosis through the ROS/AKT/GSDME axis, offering a theoretical basis for future PDAC treatment.
丝裂原活化蛋白激酶激酶（MEK）突变在胰腺导管腺癌（PDAC）中普遍存在，但许多MEK抑制剂会意外激活蛋白激酶B（AKT）。我们提出了一种有前景的PDAC治疗策略，即将MEK抑制剂曲美替尼与新枝菌素（NBT，一种来自……的天然化合物）联合使用。我们的结果表明，这种联合用药通过诱导gasdermin E（GSDME）介导的焦亡和凋亡显著阻碍细胞生长。GSDME在PDAC组织中过表达且与组织学分化相关，这突出了焦亡在PDAC中的作用。RNA测序结果表明，磷酸肌醇3激酶/蛋白激酶B（PI3K/AKT）信号通路是联合治疗的主要靶点。机制研究表明，联合用药有效降低了总AKT水平和磷酸化AKT水平，从而抑制了蛋白激酶B/IκB激酶（AKT/IKK）和蛋白激酶B/雷帕霉素哺乳动物靶点（AKT/mTOR）信号通路。此外，联合用药破坏了mTOR复合物2（mTORC2），阻止了曲美替尼诱导的AKT激活。微小RNA测序分析表明，联合用药通过上调miR-149-5p降低了AKT水平。进一步研究表明，联合用药增加了细胞内活性氧（ROS），而N-乙酰半胱氨酸（NAC，一种ROS清除剂）逆转了细胞生长抑制和AKT抑制。在体内，联合用药通过诱导焦亡和凋亡显著抑制肿瘤生长，效果优于吉西他滨。我们的研究结果为联合使用NBT和曲美替尼通过ROS/AKT/GSDME轴诱导焦亡和凋亡的潜力提供了新见解，为未来PDAC治疗提供了理论依据。
