Abstract
BACKGROUND: Identification of molecular biomarkers through comprehensive multiomics analyses is essential for the implementation of precision medicine. METHODS: To evaluate the association of each gene with sensitivity or resistance to multiple drugs, we adopted a quantitative metric, the drug response score (DRS), and examined the pharmacotranscriptomic characteristics of genes. We performed comprehensive integrative analyses of multiple independent datasets [Cancer Therapeutics Response Portal (CTRP), Profiling Relative Inhibition Simultaneously in Mixtures (PRISM), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA)] in the process of screening, proof, and validation of our findings. RESULTS: Through a comprehensive pharmacotranscriptomics approach, we found that TRIM51-high cancer cell lines (CCLs) are highly sensitive to multiple BRAF-MEK inhibitors. The association was preserved even when the analysis was restricted to BRAF-mutant melanoma CCLs, indicating the potential of TRIM51 as a BRAF mutation-independent predictive biomarker. Moreover, the expression level of TRIM51 faithfully represented the degree of post-treatment activity and resistance upon treatment with BRAF-MEK inhibitors both in vitro and in clinical situations, suggesting its application as a surrogate marker for the pharmacological activity of BRAF-MEK inhibitors. In addition, the high expression levels of TRIM51 were significantly associated with worse prognosis and immuno-resistance features in melanoma, indicating its role as a prognostic marker. CONCLUSIONS: Our findings revealed a novel role for TRIM51 as a multiuse biomarker in melanoma. The strategy of this study will motivate the development of novel clinical markers.