Large-scale And High-resolution Mass Spectrometry-based Proteomics Profiling Defines Molecular Subtypes Of Esophageal Cancer For Therapeutic Targeting

Esophageal cancer(EC)is one of the most aggressive cancer types and is the fourth leading cause of cancer-related deaths in China.Although treatments have greatly improved in the past years,the 5-year overall survival(OS)rate of EC remains in the range of 15-25%,patients largely benefit from early diagnosis.Several genomic analyses in EC have been performed to link genomic alterations with phenotypes,revealing several driver genes,such as TP53,RB1,ZNF750,NOTCH1,FAT1,and NFE2L2,with high frequencies of mutations.However,unlike breast and gastric cancer,which have improved treatment options based on well-established molecular subtypes,no molecular subtypes have been identified for EC that can assist patient stratification and therapeutic development,hindering the development of effective strategies for treatment.To define molecular subtypes of EC,we performed mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues,revealing a catalog of proteins and phosphosites that are dysregulated in ECs.The EC cohort was stratified into two molecular subtypes—S1 and S2—based on proteomic analysis,with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins,and being more aggressive.Moreover,we identified a subtype signature composed of ELOA and SCAF4,and constructed a subtype diagnostic and prognostic model.Potential drugs were predicted for treating patients of S2 subtype,and three candidate drugs Sulconazole,Menadione and GW8510)were validated to inhibit EC.Taken together,our proteomic analysis defined molecular subtypes of EC,thus providing a potential therapeutic outlook for improving disease outcomes inpatients with EC.