Background: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to
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 theseunbiased 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.
Lund University, Faculty of Medicine, Department of Translational Medicine, Clinical Chemistry, Malmö, Lunds universitet, Medicinska fakulteten, Institutionen för translationell medicin, Klinisk kemi, Malmö, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Mass Spectrometry, Clinical Protein Science and Imaging, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Masspektrometri, Clinical Protein Science and Imaging, Originator, Lund University, Faculty of Engineering, LTH, Departments at LTH, Department of Biomedical Engineering, Division for Biomedical Engineering, Lunds universitet, Lunds Tekniska Högskola, Institutioner vid LTH, Institutionen för biomedicinsk teknik, Avdelningen för biomedicinsk teknik, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Mass Spectrometry, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Masspektrometri, Originator, Lund University, Profile areas and other strong research environments, Other Strong Research Environments, LUCC: Lund University Cancer Centre, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Övriga starka forskningsmiljöer, LUCC: Lunds universitets cancercentrum, Originator
