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Peptide Degrader-Based Targeting of METTL3/14 Improves Immunotherapy Response in Cutaneous Melanoma
Hong Han1, Zenghui Li1, Yuqing Feng1
1Affiliated Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, P. R. China.
Abstract:
METTL3 has emerged as a promising therapeutic target in cancer treatment, although its oncogenic functions in melanoma development and potential for therapeutic targeting drug have not been fully explored. In this study, we define the oncogenic role of METTL3 in melanoma development and progression. Building on this insight, we examine our recently designed peptide inhibitor RM3, which targets the binding interface of METTL3/14 complex for disruption and subsequent ubiquitin-mediated proteasomal degradation via the E3 ligase STUB1. RM3 treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno-related genes following RM3-mediated suppression of METTL3/14 N6-methyladenosine (m6A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of RM3 with anti-PD-1 antibody results in significantly higher beneficial tumor response in vivo, with a good safety profile. Collectively, these findings not only delineate the oncogenic role of METTL3 in melanoma but also showcase RM3, acting as a peptide degrader, as a novel and promising strategy for melanoma treatment.
Insights
This study reveals METTL3 as a key driver in melanoma development. A novel peptide inhibitor, RM3, effectively targets METTL3, showing promise for melanoma treatment and combination therapy with immunotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- METTL3 (methyltransferase-like 3) is implicated in cancer, but its specific role in melanoma progression and therapeutic targeting remains underexplored.
- Understanding METTL3's oncogenic functions is crucial for developing novel melanoma treatment strategies.
Purpose of the Study:
- To elucidate the oncogenic role of METTL3 in melanoma development and progression.
- To evaluate the efficacy of a novel peptide inhibitor, RM3, targeting the METTL3/14 complex for melanoma treatment.
- To explore the potential of RM3 in combination with immunotherapy.
Main Methods:
- Investigated the oncogenic role of METTL3 in melanoma.
- Designed and tested peptide inhibitor RM3, which induces METTL3/14 complex degradation via STUB1.
- Assessed RM3's effects on melanoma cell proliferation, migration, invasion, and apoptosis in vitro and in vivo.
- Performed transcriptomic analysis to identify downstream effects of METTL3 inhibition.
- Evaluated combination therapy of RM3 with anti-PD-1 antibody.
Main Results:
- METTL3 plays a significant oncogenic role in melanoma development and progression.
- RM3 treatment effectively reduced melanoma cell proliferation, migration, and invasion, while inducing apoptosis.
- RM3-mediated suppression of METTL3/14 N6-methyladenosine (m6A) methyltransferase activity altered immuno-related gene expression.
- Combination therapy with RM3 and anti-PD-1 antibody demonstrated enhanced tumor response in vivo with a favorable safety profile.
Conclusions:
- METTL3 is a critical oncogene in melanoma.
- RM3, a peptide degrader, represents a novel and effective therapeutic strategy for melanoma.
- The combination of RM3 with immunotherapy holds significant potential for improving melanoma treatment outcomes.
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