Identification of Potential BRAF Inhibitor Joint Therapy Targets in PTC based on WGCAN and DCGA.

As the most common mutation in papillary thyroid cancer (PTC), B-type Raf kinase V600E mutation ( ) has become an important target for the clinical treatment of PTC. However, the clinical application still faces the problem of resistance to BRAF inhibitors (BRAFi). Therefore, exploring BRAF-associated prognostic factors to providing potential joint targets is important for combined targeted therapy with BRAFi. In this study, we combined transcript data and clinical information from 199 wild-type ( ) patients and 283 mutant patients collected from The Cancer Genome Atlas (TCGA), and screened 455 BRAF- associated genes through differential analysis and weighted gene co-expression network analysis. Based on these -associated genes, we performed functional enrichment analysis and co-expression differential analysis and constructed a core co-expression network. Next, genes in the differential co-expression network were used to predict drugs for therapy in the crowd extracted expression of differential signatures (CREEDS) database, and the key genes were selected based on the hub co-expression network through survival analyses and receiver operating characteristic (ROC) curve analyses. Finally, we obtained eight BRAF -associated biomarkers with both prognostic and diagnostic values as potential BRAFi joint targets, including , , , , , , , and . Among these genes, FN1, MET, PROS1, and were validated through GEO database. Two novel biomarkers, PROS1 and , were further validated by qRT-PCR experiment. Besides, we obtained four potential targeted drugs that could be used in combination with BRAFi to treat PTC, including MET inhibitor, ERBB3 inhibitor, anti-NaPi2b antibody-drug conjugate, and carboplatin through literature review. The study provided potential drug targets for combination therapy with BRAFi for PTC to overcome the drug resistance for BRAFi.