Enterprise AI Analysis
Unveiling Brigatinib's Pharmacological Mechanism in ALK+ NSCLC Brain Metastases with Systems Biology & AI
Brain metastases (BM) are a critical challenge in ALK+ Non-Small Cell Lung Cancer (NSCLC). This study leverages in silico systems biology and artificial intelligence to map brigatinib's multifaceted mechanism, offering precision insights into its effects on both primary tumors and established brain metastases.
Key Insights for Oncology & Drug Development
Our AI-driven analysis provides a comprehensive understanding of brigatinib's mechanism of action, predicting its significant impact on metastatic processes in ALK+ NSCLC. These insights pave the way for optimized treatment strategies and biomarker discovery.
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Model Accuracy
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PT Metastatic Effectors Modulated
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BM Metastatic Effectors Modulated
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Primary Therapeutic Targets
Deep Analysis & Enterprise Applications
Select a topic to dive deeper, then explore the specific findings from the research, rebuilt as interactive, enterprise-focused modules.
Brigatinib's Action in Primary Tumors with Metastatic Capability
Our models predict brigatinib's mechanism of action (MoA) in primary tumors primarily driven by the modulation of EGFR and IGF1R downstream pathways. This leads to the regulation of several migration-associated effector proteins, with IGF1R, ERBB2, FAK1, ERK, PRKCA, STAT3, and AKT acting as key triggering nodes.
Specifically, brigatinib's effect on the primary tumor appeared to arise from a downregulation of STAT5/STAT3, CXCR4, ETS1, AKT3, CTNB1, and ERBB2/MAPK, coupled with an activation of CADH1. These modulations collectively impact cell proliferation, migration, and invasion of NSCLC cells.
Brigatinib's Impact on Established Brain Metastases
In established brain metastases (BM), brigatinib's modulation on effectors seemed to be derived from a downregulation of YAP1, FGFR1, ABL1, CTNB1, NFKB1, and the PI3K/AKT/mTOR pathways. The main known target, ALK, was also identified as a protein effector in BM, reinforcing its critical role.
NFKB was revealed as a significant triggering node, suggesting its modulation is integral to regulating other BM effectors. Additional effectors like ETS1, CXCR4, VEGFC, CCR7, VCAM1, IL1B, LCK, IL6, and CTLA4 were also found to be modulated, demonstrating a comprehensive impact on BM progression.
Quantitative Impact of Brigatinib's Multi-Kinase Targets
Brigatinib's potential to prevent pathophysiological processes in NSCLC and BM is mainly driven by five of its six primary targets: IGF1R, EGFR, FLT3, ALK, and ROS1. The modulation of FER, by contrast, showed a minor contribution to these metastatic processes.
Our analysis quantified this impact: 59.3% of 145 effectors in primary tumors with metastatic capability and 59.6% of 114 effectors in brain metastases were reversed with activations greater than or equal to 10.1. This highlights the broad and potent influence of brigatinib across key oncogenic pathways.
Robustness and Corroboration of Mechanistic Models
The models generated through TPMS demonstrated high internal consistency with established pharmacological and pathophysiological knowledge, achieving mean accuracies above 94% against the training set. This high degree of accuracy reassures the validity of our analysis.
Further corroboration was achieved by comparing observed modulations with known bioflags and publicly available gene expression datasets. Brigatinib was predicted to significantly modulate 89 differentially expressed genes (DEGs), with 61 in primary tumors and 63 in brain metastases, including crucial effectors such as ETS1, CXCR4, VEGFC, CCR7, VCAM1, IL1B, LCK, IL6, and CTLA4. This reinforces the models' robustness and their ability to accurately reflect brigatinib's therapeutic effects.
Brigatinib's Primary Drivers in Metastasis
5 Key Targets Driving Anti-Metastatic ActivityOur analysis identifies IGF1R, EGFR, FLT3, ALK, and ROS1 as the predominant molecular targets through which brigatinib exerts its anti-metastatic effects in ALK+ NSCLC, influencing both primary tumor progression and brain metastasis control.
Enterprise Process Flow: TPMS Methodology
Input Data Compilation (ALK+ NSCLC & Brigatinib)
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TPMS Model Construction (Systems Biology & AI)
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Simulate Brigatinib MoA (Primary Tumor)
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Simulate Brigatinib MoA (Brain Metastasis)
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Unveil Mechanistic Pathways & Key Proteins
| Feature | Brigatinib Profile | Implication for ALK+ NSCLC Management |
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| Primary Target | ALK |
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| Additional Kinase Targets | IGF1R, EGFR, FLT3, ROS1, FER |
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| Intracranial Efficacy | Superior in ALTA-1L trial (HR=0.29 for BM) |
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| Mechanism of Action Scope | Modulates a broad set of metastasis-related proteins in PT & BM |
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Strategic Outlook: Optimizing Brigatinib in ALK+ NSCLC
The detailed mechanistic insights provided by our AI models offer a blueprint for optimizing brigatinib's use in ALK+ NSCLC. Understanding its multifaceted action through targets like IGF1R, EGFR, FLT3, ALK, and ROS1 supports its crucial role in preventing metastatic progression and achieving intracranial disease control, a significant clinical benefit.
These findings can guide the development of biomarker-driven strategies for patient selection, inform future combination therapies to overcome resistance mechanisms, and refine treatment guidelines. The deeper understanding of brigatinib's impact on CNS involvement provides a strong foundation for advanced oncology practices and patient monitoring.
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