Research Papers:

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

Hae Ryung Chang, Seungyoon Nam, Jinhyuk Lee, Jin-Hee Kim, Hae Rim Jung, Hee Seo Park, Sungjin Park, Young Zoo Ahn, Iksoo Huh, Curt Balch, Ja-Lok Ku, Garth Powis, Taesung Park, Jin-Hyun Jeong and Yon Hui Kim _

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Oncotarget. 2016; 7:81435-81451. https://doi.org/10.18632/oncotarget.12963

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Hae Ryung Chang1,2,*, Seungyoon Nam1,3,*, Jinhyuk Lee4,5,*, Jin-Hee Kim6,*, Hae Rim Jung1, Hee Seo Park7, Sungjin Park1,3, Young Zoo Ahn1, Iksoo Huh8, Curt Balch9, Ja-Lok Ku10, Garth Powis11, Taesung Park8, Jin-Hyun Jeong6, Yon Hui Kim1,12

1New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea

2Research Institute of Women’s Health, Sookmyung Women’s University, Seoul, Republic of Korea

3College of Medicine, Gachon University, Incheon, Republic of Korea

4Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

5Department of Nanobiotechnology and Bioinformatics, Korea University of Science and Technology, Daejeon, Republic of Korea

6College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea

7Animal Sciences Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea

8Department of Statistics, Seoul National University, Seoul, Republic of Korea

9Bioscience Advising, Ypsilanti, MI, USA

10Korean Cell Line Bank, Seoul National University, Seoul, Republic of Korea

11Cancer Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

12Discovery Biology, CrystalGenomics Inc., Seongnam-si, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Yon Hui Kim, email: [email protected]

Jin-Hyun Jeong, email: [email protected]

Taesung Park, email: [email protected]

Keywords: gastric cancer, RHOA, G-protein, biomarker, therapeutic target

Received: July 11, 2016    Accepted: October 17, 2016    Published: October 28, 2016


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.

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