Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Department of Gastrointestinal Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang, 310009, PR China.
Eur J Pharmacol. 2021 Apr 5;896:173879. doi: 10.1016/j.ejphar.2021.173879. Epub 2021 Jan 28.
Gastric cancer (GC), known for high morbidity and mortality, is poorly prognosed with traditional chemotherapy and biological agents. Current studies have found that over-activation of AKT is a common molecular characteristic in GC. Although the development of this targeted inhibitor has entered clinical phases, limited success is reported because of its compensatory signaling pathways. Here, we found that GC cell lines with high phosphorylation of AKT show different sensitivity to AKT inhibitors (AKTis), but a reduction of p-GSK3β related sensitivity of AKTis in GC cells. Besides, we revealed that Ceritinib exerted a strongly synergistic antitumor effect with AKT inhibitors both in vitro and in vivo. Obviously, Ceritinib improved the sensitivity of Capivasertib (AZD5363, AKTs) and Afuresertib (GSK2110183, AKTis) in gastric cancer cells, as illustrated by a significant reduction in the GC cell proliferation and enhanced apoptosis. The drug combination showed tumor regression in BALB/c (nu/nu) mouse MKN45 (Gastric cancer), tumor model. Also, the combination strategy indicated significantly low p-AKT levels due to AKTis compensation and reduced the levels of p-GSK3β in both GC cell lines and GC patient-derived cells. These findings may provide a novel combination strategy for gastric cancer treatment.
胃癌（GC）发病率和死亡率高，传统的化疗和生物制剂治疗预后较差。目前的研究发现，AKT 的过度激活是 GC 的一个常见分子特征。尽管这种靶向抑制剂的开发已经进入临床阶段，但由于其补偿性信号通路，报道的疗效有限。在这里，我们发现 AKT 磷酸化水平高的 GC 细胞系对 AKT 抑制剂（AKTi）的敏感性不同，但 GC 细胞中 AKTi 的 p-GSK3β 相关敏感性降低。此外，我们还揭示了塞利替尼在体外和体内与 AKT 抑制剂联合具有强烈的协同抗肿瘤作用。显然，Ceritinib 降低了 Capivasertib（AZD5363，AKTs）和 Afuresertib（GSK2110183，AKTi）在胃癌细胞中的敏感性，GC 细胞增殖显著减少，凋亡增强。该药物组合在 BALB/c（nu/nu）小鼠 MKN45（胃癌）肿瘤模型中显示出肿瘤消退。此外，由于 AKTi 的补偿作用，联合策略显著降低了 GC 细胞系和 GC 患者来源细胞中 p-AKT 的水平，并降低了 p-GSK3β 的水平。这些发现可能为胃癌治疗提供一种新的联合策略。
