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Enhancing immunotherapy efficacy in colorectal cancer: targeting the FGR-AKT-SP1-DKK1 axis with DCC-2036 (Rebastinib)
Xiguang Chen1,2,3, Qiting Zeng4, Liyang Yin1
1The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
Abstract:
This research demonstrates that DCC-2036 (Rebastinib), a potent third-generation tyrosine kinase inhibitor (TKI), effectively suppresses tumor growth in colorectal cancer (CRC) models with functional immune systems. The findings underscore the capacity of DCC-2036 to enhance both the activation and cytotoxic functionality of CD8+ T cells, which are crucial for facilitating anti-tumor immune responses. Through comprehensive multi-omics investigations, significant shifts in both gene and protein expression profiles were detected, notably a marked decrease in DKK1 levels. This reduction in DKK1 was linked to diminished CD8+ T cell effectiveness, correlating with decreased FGR expression. Moreover, our findings identify FGR as a pivotal modulator that influences DKK1 expression via the PI3K-AKT-SP1 signaling cascade. Correlative analysis of clinical specimens supports the experimental data, showing that increased levels of FGR and DKK1 in CRC tissues are associated with inferior clinical outcomes and reduced efficacy of immunotherapeutic interventions. Consequently, targeting the FGR-AKT-SP1-DKK1 pathway with DCC-2036 could potentiate immunotherapy by enhancing CD8+ T cell functionality and their tumor infiltration. This strategy may contribute significantly to the refinement of therapeutic approaches for CRC, potentially improving patient prognoses.
Insights
DCC-2036 (Rebastinib) enhances anti-tumor CD8+ T cell responses in colorectal cancer (CRC) models. This tyrosine kinase inhibitor (TKI) targets the FGR-AKT-SP1-DKK1 pathway, potentially improving immunotherapy efficacy for CRC patients.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Colorectal cancer (CRC) remains a significant health challenge with limited treatment options.
- Tumor immune evasion is a major hurdle for effective cancer immunotherapy.
- CD8+ T cells are critical for orchestrating anti-tumor immune responses.
Purpose of the Study:
- To investigate the anti-tumor effects of DCC-2036 (Rebastinib) in colorectal cancer (CRC) models.
- To elucidate the mechanisms by which DCC-2036 modulates the tumor immune microenvironment.
- To explore the potential of DCC-2036 in combination with immunotherapy for CRC treatment.
Main Methods:
- Utilized colorectal cancer (CRC) models with functional immune systems.
- Conducted comprehensive multi-omics investigations (gene and protein expression).
- Performed correlative analysis of clinical specimens from CRC patients.
Main Results:
- DCC-2036 suppressed tumor growth and enhanced CD8+ T cell activation and function.
- DCC-2036 treatment led to decreased DKK1 levels, linked to reduced CD8+ T cell effectiveness.
- FGR was identified as a key regulator of DKK1 expression via the PI3K-AKT-SP1 pathway.
- Increased FGR and DKK1 levels in CRC tissues correlated with poor outcomes and immunotherapy resistance.
Conclusions:
- DCC-2036 potentiates anti-tumor immunity by enhancing CD8+ T cell functionality in CRC.
- Targeting the FGR-AKT-SP1-DKK1 pathway with DCC-2036 may overcome immunotherapy resistance in CRC.
- DCC-2036 represents a promising therapeutic strategy to improve CRC treatment outcomes and immunotherapy efficacy.
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