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.
Bibliographical noteFunding Information:
This study was supported by grants from the National Cancer Center of the Republic of Korea, NCC-1210350-3, NCC-1510500-1 National Research Foundation of Korea (MSIP) 2015R1A2A1A10052661 (to YHK); National Research Foundation of Korea 2015R1D1A1A01059381 (HRC); National Cancer Center of the Republic of Korea, NCC-1210460, NCC-1510140-1, the Gachon University Gil Medical Center (Grant number: 2016-06) (to SN); Bio-Synergy Research Project (2013M3A9C4078158) of the Ministry of Science, ICT and Future Planning through the National Research Foundation and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2165) (to TP); and from the Korean Research Institute of Bioscience and the Biotechnology Research Initiative Program (to JL).
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