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

Abstract

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.

Evaluation of the Prognostic Value of Solute Carrier Family 34 Member 2 “SLC34A2” in Papillary Thyroid Carcinoma: An Immunohistochemical Study

“…Backward stepwise Cox regression analysis indicated that SLC34A2 IHC expression as well as age and lymph node status at presentation was independent factors affecting the DFS of PTC cases studied herein. This was in agreement with Han et al [14] whose PTC cases that showed upregulated SLC34A2 gene expression had shorter relapse-free survival. Similarly, SLC34A2 expression has been reported as an independent factor for shorter DFS in CRC and bladder cancer [23].…”

“…SLC34A2 is among the genes that have previously been linked to PTCs associated with the BRAF mutation. Previous studies have shown elevated SLC34A2 gene expression in PTC patients associated with BRAF v600E mutations [8,14]. Moreover, another study has even demonstrated that the SLC34A2 gene is downregulated in BRAF wild-type PTCs [15].…”

“…Thus, anti-NaPi2b ADCs might be a promising therapeutic modality for the treatment of PTC. A recent study associating anti-NaPi2b antibody with BRAF mutations provided a theoretical basis for SLC34A2 inhibition and BRAF inhibition combined therapy which if validated and implemented might provide better management of PTC [14].…”

Expression Profile and Diagnostic Significance of MicroRNAs in Papillary Thyroid Cancer

“…Masago et al described the effect of EGFR -activating mutations on PTC development [ 74 ]. Inhibitors of ERRB3, which is also known as a proto-oncogene and a member of the EGFR family, may be effective in the treatment of PTC [ 75 ]. Alternatively, the oncogene KIT , described for its role in PTC and other cancers, encodes a receptor tyrosine kinase that affects cellular growth and differentiation [ 76 ].…”

BRAF-activated WT1 contributes to cancer growth and regulates autophagy and apoptosis in papillary thyroid carcinoma

“…This result may help improve the clinical outcomes for PTC patients and indicates possibilities for personalized treatment. BRAF mutations are the most frequent mutation subtypes in PTC patients, and targeting BRAF mutants to develop targeted therapy drugs may be an effective method to overcome PTC [ 30 ]. In this study, we comprehensively analyzed the differentially expressed genes in BRAF MT and BRAF WT PTC tissue samples obtained from a TCGA patient cohort.…”