MTHFD2-Targeting Peptide Decoy for Chemotherapy-Resistant Cancers

Application

An engineered decoy peptide, DMp39, targeting DLAT-MTHFD2 interaction, as a sensitizer for chemotherapy resistant cancer treatment.

Key Benefits

• Restores chemotherapy sensitivity in resistant tumors.
• Targets the DLAT-MTHFD2 pathway with high specificity and minimal off-target toxicity.

Market Summary

Chemotherapy resistance remains a major barrier to effective cancer treatment, driving disease progression and limiting long-term patient outcomes. Emerging evidence links dysregulated protein acetylation to resistance mechanisms, though the underlying molecular pathways are not yet fully defined. At the same time, demand is increasing for targeted therapies that act rapidly and selectively, particularly in oncology. Peptide-based therapeutics are gaining traction as a promising modality, supported by advances in precision medicine and biomarker-driven treatment strategies. Within this evolving landscape, there is a significant unmet need for approaches that can restore chemotherapy sensitivity through novel mechanisms. Targeting mitochondrial pathways represents a compelling and underexplored opportunity to overcome resistance. Innovations that address these challenges have the potential to redefine treatment paradigms for resistant cancers and improve patient response to existing therapies.

Technical Summary

Emory researchers have developed DMp39, a cell-permeable decoy peptide designed to overcome chemotherapy resistance in cancer. It works by disrupting a newly discovered interaction between two mitochondrial proteins, DLAT and MTHFD2, that drives chemotherapy resistance. Blocking DLAT-mediated acetylation of MTHFD2 at lysine-44 with DMp39 restores sensitivity to cisplatin and promotes cancer cell death with minimal toxicity offering a promising new class of peptide-based cancer therapeutics.

Development Stage

• In vitro and in vivo study results available.
• The inventors have synthesized a more stable analog of the peptide and are evaluating it in combination with multiple chemotherapy and immunotherapy agents to determine optimal treatment strategies for cancer.

Publication Hwang, J. S., Kang, J., Kim, J., Eun, K., West, S., Bacho, H. E., Avalos, V., Shuff, S., Shin, D. M., Saba, N. F., Magliocca, K. R., Qu, C. K., Fu, H., Ramalingam, S. S., Ivanov, A. A., Hitosugi, T., & Kang, S. (2025). Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling. *Nature Communications, 16*, 8932. https://doi.org/10.1038/s41467-025-63892-3