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GDC-0349 inhibits non-small cell lung cancer cell growth
Han Yang1, Jun Zhao2, Mengjing Zhao3
1Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Abstract:
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.
Insights
GDC-0349, an mTOR inhibitor, effectively reduced non-small cell lung cancer (NSCLC) growth through both mTOR-dependent and independent pathways. It also induced apoptosis and inhibited tumor growth in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) remains a major cause of cancer mortality, necessitating novel therapeutic strategies.
- Targeting the mTOR pathway is a promising approach for NSCLC treatment.
Purpose of the Study:
- To investigate the efficacy and mechanisms of GDC-0349, a novel ATP-competitive mTOR inhibitor, in NSCLC.
- To elucidate the Akt-mTOR-dependent and -independent pathways involved in GDC-0349's anti-cancer effects.
Main Methods:
- In vitro studies using NSCLC cell lines (A549, primary human NSCLC cells) treated with GDC-0349.
- Assessment of cell growth, proliferation, cell cycle, apoptosis, migration, invasion, and signaling pathway activation (Akt-mTOR, SphK1, JNK).
- In vivo studies using NSCLC xenograft mouse models treated with GDC-0349.
Main Results:
- GDC-0349 inhibited NSCLC cell growth, proliferation, migration, invasion, and induced apoptosis.
- GDC-0349 blocked Akt-mTORC1/2 activation but also showed cytotoxicity in Akt1-knockout cells, indicating Akt-mTOR-independent effects.
- GDC-0349 induced SphK1 inhibition, ceramide accumulation, JNK activation, and oxidative injury, which were implicated in its apoptotic effects.
- GDC-0349 significantly inhibited NSCLC xenograft growth in vivo, with associated molecular changes in tumor tissues.
Conclusions:
- GDC-0349 demonstrates potent anti-NSCLC activity through both Akt-mTOR-dependent and -independent mechanisms.
- GDC-0349's efficacy involves induction of apoptosis via SphK1 inhibition, JNK activation, and oxidative stress.
- GDC-0349 represents a promising therapeutic agent for NSCLC treatment.
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