RRC ID 51923
Author Chang HR, Nam S, Lee J, Kim JH, Jung HR, Park HS, Park S, Ahn YZ, Huh I, Balch C, Ku JL, Powis G, Park T, Jeong JH, Kim YH.
Title Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer.
Journal Oncotarget
Abstract Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer "Big Data" has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of "hit" compounds.
Volume 7(49)
Pages 81435-81451
Published 2016-12-6
DOI 10.18632/oncotarget.12963
PII 12963
PMID 27806312
PMC PMC5348404
MeSH Animals Antineoplastic Agents / pharmacology Asian Continental Ancestry Group / genetics Biomarkers, Tumor / genetics* Biomarkers, Tumor / metabolism Cell Line, Tumor Cell Proliferation Computational Biology Databases, Genetic Enzyme Inhibitors / pharmacology European Continental Ancestry Group / genetics Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Genetic Association Studies Humans Mice, SCID Molecular Targeted Therapy RNA Interference Republic of Korea Signal Transduction Stomach Neoplasms / drug therapy Stomach Neoplasms / ethnology Stomach Neoplasms / genetics* Stomach Neoplasms / pathology Time Factors Transcriptome Transfection Tumor Burden Up-Regulation Xenograft Model Antitumor Assays rhoA GTP-Binding Protein / antagonists & inhibitors rhoA GTP-Binding Protein / genetics* rhoA GTP-Binding Protein / metabolism rhoB GTP-Binding Protein / genetics rhoB GTP-Binding Protein / metabolism
Human and Animal Cells MKN45(RCB1001)