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

YaLi Han; XiaQing Yu; YuZhen Yin; Zhongwei Lv; ChengYou Jia; Yina Liao; Hongyan Sun; Tie Liu; Lele Cong; ZhaoLiang Fei; Da Fu; Xianling Cong; Shen Qu

doi:10.7150/jca.51551

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

J Cancer. 2021 Jan 21;12(6):1779-1791. doi: 10.7150/jca.51551. eCollection 2021.

Authors

YaLi Han¹, XiaQing Yu², YuZhen Yin², Zhongwei Lv², ChengYou Jia¹, Yina Liao¹, Hongyan Sun³, Tie Liu³, Lele Cong³, ZhaoLiang Fei⁴, Da Fu⁵, Xianling Cong³, Shen Qu¹

Affiliations

¹ Shanghai Center for Thyroid Disease, Shanghai Tenth People's Hospital, Shanghai, China.
² Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
³ Department of biobank, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People's Republic of China.
⁴ Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
⁵ Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

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^V600E -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.

Keywords: BRAF; biomarkers; papillary thyroid cancer; targeted drugs.