Related Experiment Video
Updated: Jun 4, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma
Indira Pla1,2, Botond L Szabolcs3,4,5,6, Petra Nikolett Péter3,4,5,7
1Department of Biomedical Engineering, Faculty of Engineering, LTH, Lund University, Lund, Sweden.
Background:
The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.
Objective:
Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.
Methods:
Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC, and AKT1, across five distinct MM subtypes. These proteins are potential drug targets applicable to one or multiple MM subtypes. Additionally, by integrating proteogenomic profiles obtained from MM subtypes with MM cell line dependency and drug sensitivity data, we identified a total of 162 potentially targetable genes. Lastly, we identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype.
Results:
Employing these unbiased approaches, we have uncovered compounds targeting ferroptosis demonstrating a striking 30× fold difference in sensitivity among different subtypes.
Conclusions:
Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.
Insights
This study identifies new drug targets and compounds for malignant melanoma (MM) by analyzing proteogenomic data. Findings reveal potential therapeutic strategies and combination therapies to overcome treatment resistance in MM.
Area of Science:
- Oncology
- Proteogenomics
- Drug Discovery
Background:
- Immune-checkpoint inhibitors (PD1, CTLA4) transformed malignant melanoma (MM) treatment.
- Therapy resistance remains a significant challenge in MM management.
Purpose of the Study:
- To identify novel druggable targets in MM.
- To predict treatment efficacy and resistance patterns.
- To discover new therapeutic strategies for MM.
Main Methods:
- Proteogenomic data mining of MM subtypes.
- Analysis of 82 cancer drug structures.
- Integration of proteogenomic profiles with cell line dependency and drug sensitivity data.
Main Results:
- Identified nine candidate hub proteins (e.g., mTOR, EGFR, AKT1) as potential MM drug targets.
- Discovered 162 potentially targetable genes across MM subtypes.
- Uncovered compounds targeting ferroptosis with a 30-fold sensitivity difference among subtypes.
Conclusions:
- Proteomic profiling enables melanoma sample stratification.
- Novel therapeutic strategies and combination therapies are suggested.
- Offers new prospects for overcoming MM treatment resistance.
