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) 是癌症相关人类死亡的主要原因，显然需要新的治疗干预。GDC-0349 是一种有效的选择性 ATP 竞争性 mTOR 抑制剂。在 A549 细胞和原代人类 NSCLC 细胞中，GDC-0349 抑制细胞生长、增殖、细胞周期进程、迁移和侵袭，同时诱导显着的细胞凋亡激活。尽管 GDC-0349 阻断了 NSCLC 细胞中 Akt-mTORC1/2 的激活，但它也在 Akt1 敲除的 A549 细胞中发挥了细胞毒性。此外，通过组成型活性 Akt1 恢复 Akt-mTOR 激活仅部分减弱 GDC-0349 诱导的 A549 细胞凋亡，表明存在 Akt-mTOR 独立机制。在 NSCLC 细胞中，GDC-0349 诱导鞘氨醇激酶 1 (SphK1) 抑制、神经酰胺积累、JNK 活化和氧化损伤。相反，N-乙酰半胱氨酸、JNK 抑制剂和 1-磷酸鞘氨醇可减轻 GDC-0349 诱导的 NSCLC 细胞凋亡。在体内，每天口服 GDC-0349 可有效抑制小鼠的 NSCLC 异种移植物生长。在施用 GDC-0349 的 NSCLC 异种移植组织中检测到 Akt-mTOR 失活、SphK1 抑制、JNK 激活和氧化应激。总之，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。