Tyrosine aminoacyl-tRNA synthetase sensitizes breast cancer to chemotherapy through a necroptosis-mediated mechanism.

40 Background: A complete response to chemotherapy for most cancer patients is, and there are many complications caused by this toxic therapy. Therefore, we sought to determine chemotherapy responses in breast cancer at the proteome level. Methods: Candidate proteins were filtered out by the proteomic-based multiple machine-learning algorithms. Results: The MS analysis of FFPE set yielded 6,069 protein groups. The filtered dataset resulted in 539 proteins with differential abundances. We searched for biological process in the Gene Ontology (GO) enrichment analysis in each proteomic cluster. Several immune responses process, apoptotic process, DNA replication process and aminoacylation for protein translation process primarily were represented in group with complete remission. On the other hand, cell adhesion process, cytoskeleton organization process, vesicle organization process and Golgi organization process represented in breast cancer which showed poor responses to the therapy. The machine learning approaches demonstrated the highest AUC value, 0.978 (sensitivity 1.0 and specificity 0.714) with a combination of 11 proteins. Among them the finally selected tyrosine aminoacyl-tRNA synthetase (YARS) showed AUC (AUC = 0.749) in the subsequent steps of verification using immunohistochemistry in 123 patient cohorts. We identified the predictive relevance of YARS. YARS induced tumor necroptosis was greatly enhanced when it was combined synergistically with a combination of SMAC mimetics and a BCL2 inhibitor. Conclusions: This suggested that YARS expression could serve as a new therapeutic target for improving the clinical benefits of chemotherapy.