Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

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Title
Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer
Author(s)
H R Chang; S Nam; Jinhyuk Lee; J H Kim; H R Jung; H S Park; S Park; Y Z Ahn; I Huh; C Balch; J L Ku; G Powis; T Park; J H Jeong; Y H Kim
Bibliographic Citation
Oncotarget, vol. 7, no. 49, pp. 81435-81451
Publication Year
2016
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.
Keyword
BiomarkerG-proteinGastric cancerRHOATherapeutic target
ISSN
1949-2553
Publisher
Impact Journals
DOI
http://dx.doi.org/10.18632/oncotarget.12963
Type
Article
Appears in Collections:
Division of Biomedical Research > Genome Editing Research Center > 1. Journal Articles
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