Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer.
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.
New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.|Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
Hae Ryung
HR
Chang
New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.|College of Medicine, Gachon University, Incheon, Republic of Korea.
Seungyoon
S
Nam
Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Nanobiotechnology and Bioinformatics, Korea University of Science and Technology, Daejeon, Republic of Korea.
Jinhyuk
J
Lee
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.
Jin-Hee
JH
Kim
New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.
Hae Rim
HR
Jung
Animal Sciences Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.
Hee Seo
HS
Park
New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.|College of Medicine, Gachon University, Incheon, Republic of Korea.
Sungjin
S
Park
New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.
Young Zoo
YZ
Ahn
Department of Statistics, Seoul National University, Seoul, Republic of Korea.
Iksoo
I
Huh
Bioscience Advising, Ypsilanti, MI, USA.
Curt
C
Balch
Korean Cell Line Bank, Seoul National University, Seoul, Republic of Korea.
Ja-Lok
JL
Ku
Cancer Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Garth
G
Powis
Department of Statistics, Seoul National University, Seoul, Republic of Korea.
Taesung
T
Park
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.
Jin-Hyun
JH
Jeong
New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.|Discovery Biology, CrystalGenomics Inc., Seongnam-si, Republic of Korea.
Yon Hui
YH
Kim
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D044466:Asian People / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D030541:Databases, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D034622:RNA Interference; D056910:Republic of Korea; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D013997:Time Factors; D059467:Transcriptome; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D044465:White People / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein
G-protein; RHOA; biomarker; gastric cancer; therapeutic target