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Targeting S-Nitrosylation to Overcome Therapeutic Resistance in NRAS-Driven Melanoma
Jyoti Srivastava1, Sanjay Premi1
1Department of Tumor Microenvironment and Metastasis, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
Abstract:
NRAS-mutant melanoma represents a clinically challenging subset of melanoma with limited effective therapies and intrinsic resistance to targeted MEK inhibition. Recent findings highlight protein S-nitrosylation, a redox-dependent post-translational modification as a critical modulator of MEK-ERK signaling and immune evasion in this context. In this commentary, we discuss how S-nitrosylation of MAPK components, including MEK and ERK, sustains oncogenic signaling and attenuates immunogenic cell death. Targeting this modification with nitric oxide synthase (NOS) inhibitors such as L-NAME, L-NMMA and 1400w restore sensitivity of MEK inhibitor, promotes dendritic cell activation, and enhances CD8+ T cell infiltration in preclinical models such as immunogenic mouse models and individual patient derived, primary melanoma cells. We also explore the emerging role of S-nitrosylation in regulating macrophage-mediated immune surveillance and propose translational strategies for combining redox modulation with targeted and immune therapies. These insights offer a compelling framework for overcoming therapeutic resistance and reprogramming the tumor immune microenvironment to activate the cytotoxic T-cells and enhance the responses to immunotherapy in NRAS-driven cancers.
Insights
Targeting protein S-nitrosylation with nitric oxide synthase (NOS) inhibitors can overcome resistance to MEK inhibitors in NRAS-mutant melanoma. This approach enhances anti-tumor immunity and T-cell responses, offering new therapeutic strategies.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- NRAS-mutant melanoma exhibits resistance to MEK inhibitors, limiting treatment options.
- Protein S-nitrosylation is a critical regulator of MEK-ERK signaling and immune evasion in melanoma.
- S-nitrosylation sustains oncogenic signaling and reduces immunogenic cell death in this cancer type.
Purpose of the Study:
- To investigate the role of protein S-nitrosylation in NRAS-mutant melanoma.
- To explore the potential of targeting S-nitrosylation to overcome therapeutic resistance.
- To evaluate the impact of nitric oxide synthase (NOS) inhibitors on tumor immunity.
Main Methods:
- Utilized preclinical models including immunogenic mouse models and patient-derived melanoma cells.
- Investigated the effects of NOS inhibitors (L-NAME, L-NMMA, 1400w) on MEK-ERK signaling.
- Assessed changes in dendritic cell activation and CD8+ T cell infiltration.
- Explored S-nitrosylation's role in macrophage-mediated immune surveillance.
Main Results:
- Targeting S-nitrosylation with NOS inhibitors restored sensitivity to MEK inhibitors in preclinical models.
- NOS inhibition promoted dendritic cell activation and enhanced CD8+ T cell infiltration.
- S-nitrosylation was identified as a key mechanism sustaining oncogenic signaling and immune evasion.
Conclusions:
- Redox modulation via NOS inhibition presents a promising strategy to overcome therapeutic resistance in NRAS-mutant melanoma.
- Combining redox modulation with targeted and immune therapies can reprogram the tumor immune microenvironment.
- This approach holds potential for enhancing cytotoxic T-cell responses and improving immunotherapy outcomes in NRAS-driven cancers.
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