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Berbamine as potential STING inhibitor For KRAS-mutant non-small cell lung cancer
Haoxin Yan1, Jumin Huang2, Yuwei Wang3
1State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics of Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao.
Abstract:
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality. Poor prognostic results in LUAD are frequently associated with KRAS mutations and drug resistance. KRAS mutations can induce STING activation by triggering DNA damage response (DDR) activation. This persistently activated STING signaling gives rise to an immunosuppressive microenvironment, thereby complicating treatment efforts. In this study, we identified that the low-toxicity pro-apoptotic drug Berbamine (BBM) as a potential therapeutic agent for LUAD cells with KRAS mutations. BBM exhibits anti-tumor effects by triggering cell cycle arrest, enhancing senescence, and activating apoptosis. BBM also targets STING, leading to the downregulation of p-STING (Ser366) and CCL2. This in turn reduced the infiltration of M-MDSCs into the tumor microenvironment. These combined mechanisms not only suppress STING-dependent tumor growth but also remodel the immunosuppressive tumor microenvironment, thereby enhancing anti-tumor immunity. Collectively, our findings position BBM as a promising therapeutic agent for LUAD with KRAS mutations, offering a strategy to target STING-associated pathways, overcome immune suppression, and ultimately improve patient outcomes.
Insights
Berbamine (BBM) shows promise for KRAS-mutated lung adenocarcinoma (LUAD). This drug combats tumor growth by reducing immunosuppression and enhancing anti-tumor immunity, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Lung adenocarcinoma (LUAD) presents a significant challenge due to poor prognosis linked to KRAS mutations and drug resistance.
- KRAS mutations activate DNA damage response (DDR), leading to persistent STING activation and an immunosuppressive tumor microenvironment.
- This immunosuppressive environment hinders effective treatment strategies for LUAD patients.
Purpose of the Study:
- To identify a potential therapeutic agent for KRAS-mutated LUAD.
- To investigate the anti-tumor mechanisms of Berbamine (BBM) in LUAD.
- To evaluate BBM's impact on the STING pathway and tumor microenvironment.
Main Methods:
- Investigated the anti-tumor effects of Berbamine (BBM) on LUAD cells.
- Assessed BBM's impact on cell cycle arrest, senescence, and apoptosis.
- Analyzed BBM's effect on STING signaling, p-STING (Ser366), CCL2, and M-MDSC infiltration.
Main Results:
- Berbamine (BBM) demonstrated anti-tumor activity by inducing cell cycle arrest, senescence, and apoptosis in LUAD cells.
- BBM effectively targeted STING, downregulating p-STING (Ser366) and CCL2.
- Reduced CCL2 levels led to decreased M-MDSC infiltration, remodeling the tumor microenvironment.
Conclusions:
- Berbamine (BBM) is a potential therapeutic agent for KRAS-mutated LUAD.
- BBM suppresses STING-dependent tumor growth and overcomes immune suppression.
- BBM remodels the tumor microenvironment to enhance anti-tumor immunity, improving patient outcomes.
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