Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
Cell Death Dis. 2020 Nov 5;11(11):951. doi: 10.1038/s41419-020-03146-w.
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related human mortality with a clear need for new therapeutic intervention. GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor. In A549 cells and primary human NSCLC cells, GDC-0349 inhibited cell growth, proliferation, cell cycle progression, migration and invasion, while inducing significant apoptosis activation. Although GDC-0349 blocked Akt-mTORC1/2 activation in NSCLC cells, it also exerted cytotoxicity in Akt1-knockout A549 cells. Furthermore, restoring Akt-mTOR activation by a constitutively-active Akt1 only partially attenuated GDC-0349-induced A549 cell apoptosis, indicating the existence of Akt-mTOR-independent mechanisms. In NSCLC cells GDC-0349 induced sphingosine kinase 1 (SphK1) inhibition, ceramide accumulation, JNK activation and oxidative injury. Conversely, N-acetylcysteine, the JNK inhibitor and sphingosine 1-phosphate alleviated GDC-0349-induced NSCLC cell apoptosis. In vivo, daily oral administration of GDC-0349 potently inhibited NSCLC xenograft growth in mice. Akt-mTOR in-activation, SphK1 inhibition, JNK activation and oxidative stress were detected in NSCLC xenograft tissues with GDC-0349 administration. In summary, GDC-0349 inhibits NSCLC cell growth via Akt-mTOR-dependent and Akt-mTOR-independent mechanisms.
非小细胞肺癌（NSCLC）是导致人类癌症相关死亡的主要原因，因此迫切需要新的治疗干预措施。GDC-0349 是一种有效的、选择性的 ATP 竞争性 mTOR 抑制剂。在 A549 细胞和原发性人非小细胞肺癌细胞中，GDC-0349 抑制细胞生长、增殖、细胞周期进程、迁移和侵袭，同时诱导显著的细胞凋亡激活。尽管 GDC-0349 阻断了 NSCLC 细胞中的 Akt-mTORC1/2 激活，但它在 Akt1 敲除的 A549 细胞中也表现出细胞毒性。此外，通过组成型活性 Akt1 恢复 Akt-mTOR 激活仅部分减弱了 GDC-0349 诱导的 A549 细胞凋亡，表明存在 Akt-mTOR 非依赖性机制。在 NSCLC 细胞中，GDC-0349 诱导了 SphK1 抑制、神经酰胺积累、JNK 激活和氧化损伤。相反，N-乙酰半胱氨酸、JNK 抑制剂和鞘氨醇 1-磷酸减轻了 GDC-0349 诱导的 NSCLC 细胞凋亡。在体内，GDC-0349 每日口服给药可强烈抑制荷瘤小鼠的 NSCLC 移植瘤生长。在 GDC-0349 给药的 NSCLC 移植瘤组织中检测到 Akt-mTOR 失活、SphK1 抑制、JNK 激活和氧化应激。综上所述，GDC-0349 通过 Akt-mTOR 依赖性和 Akt-mTOR 非依赖性机制抑制 NSCLC 细胞生长。
