Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer.

Zhen Xiang,Xia Huang,Zhenggang Zhu,Jun Zhang,Ranlin Yan,Jiexuan Wang,Wei Cai,Yingyan Yu,Jun Ji

doi:10.3389/fphar.2018.00861

Zhen Xiang, Xia Huang + Show 7 more

Open Access

https://doi.org/10.3389/fphar.2018.00861

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Abstract

Exploring ERBB2-related pathways will help us finding sensitive molecules and potential combined therapeutic targets of ERBB2-targeted therapy for ERBB2+ gastric cancer (GC). In this study, we performed a cross-databases study focused on ERBB2+ GC. The data of ERBB2+ GC deposited in the cancer genome atlas (TCGA), gene expression omnibus (GEO), InBio MapTM, cancer cell line encyclopedia (CCLE), and cancer therapeutics response portal (CTRP) were analyzed. The correlation of expression levels of candidate and IC50 of candidate genes-targeted drugs were verified on NCI-N87 and MKN-45 GC cell lines. We found that RARA, THRA, CACNB1, and TOP2A are drug sensitive biomarkers of ERBB2-targeted treatment with FDA-approved drugs. All these genes act through Myc signaling pathway. Myc is the downstream hub gene of both ERBB2 and RARA. The expression of RARA, THRA, and CACNB1 were negatively correlated with Myc activation, while ERBB2 and TOP2A positively correlated with Myc activation. SH3BGRL3, SH3BGRL, and NRG2 were identified as potential ligands of ERBB2. The ERBB2+ GC with RARA amplification demonstrated better prognosis than those without RARA amplification, while overexpression of NRG2 and SH3BGRL correlated with poor prognosis in ERBB2+ GC. About 90% of ERBB2+ GC was compatible with chromosome instability (CIN) subtype of TCGA, which overlaps with intestinal-type GC in Lauren classification. In validating experiments, combination of Lapatinib and all-trans retinoic acid (ATRA) synergistically suppresses cell growth, and accompanied by decreased expression of MYC. In conclusions, we identified several predicting biomarkers for ERBB2-targeted therapy and corresponding histological features of ERBB2+ GC. Combination of ERBB2 antagonist or RARA agonist may be effective synergistic regimens for ERBB2+ GC.

Highlights

Gastric cancer (GC) is one of the most common cancers and the third leading cause of mortality worldwide (Ferlay et al, 2015)
Among 413 cases of gastric cancer (GC) from the cancer genome atlas (TCGA) dataset, ERBB2+ GC accounted for 14.29% (59/413 cases), and the others were ERBB2- GC (354/413 cases)
Forty-seven differential expressed genes were selected based on the likelihood ratio (LR) and P-value (LR > 100, P < 0.0001; Figure 1A)

Summary

INTRODUCTION

Gastric cancer (GC) is one of the most common cancers and the third leading cause of mortality worldwide (Ferlay et al, 2015). A small-molecule inhibitor of ERBB2, plus paclitaxel demonstrated activity in the second-line treatment of ERBB2+ GC (Hecht et al, 2016). Finding additional therapeutic targets for combined therapy will benefit more ERBB2+ GC patients. Paroni et al (2012) reported that combination of RARA agonist and ERBB2-targeted drug demonstrated a synergistic anticancer activity in breast cancer. It suggested that some novel therapeutic targets for ERBB2+ GC may harbor on chromosome 17. We analyzed ERBB2-related pathways and explored potential drug sensitivity biomarkers that could be used as reference for targeted therapy of ERBB2+ GC

MATERIALS AND METHODS

RESULTS

DISCUSSION