As the most common mutation in papillary thyroid cancer (PTC), B-type Raf kinase V600E mutation (
BRAF
V600E
) 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
V600E
-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
BRAF
wild-type (
BRAF
WT
) patients and 283
BRAF
V600E
mutant patients collected from The Cancer Genome Atlas (TCGA), and screened 455 BRAF
V600E
- associated genes through differential analysis and weighted gene co-expression network analysis. Based on these
BRAF
V600E
-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
V600
E
-associated biomarkers with both prognostic and diagnostic values as potential BRAFi joint targets, including
FN1
,
MET
,
SLC34A2
,
NGEF
,
TBC1D2
,
PLCD3
,
PROS1
, and
NECTIN4
. Among these genes, FN1, MET, PROS1, and
TBC1D2
were validated through GEO database. Two novel biomarkers, PROS1 and
TBC1D2
, 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.