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Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer
Hae Ryung Chang1,2, Seungyoon Nam1,3, Jinhyuk Lee4,5
1New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Republic of Korea.
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.
Insights
Gastric cancer (GC) therapies need biomarkers. Research shows RHOA (Ras homolog family member A) pathway targeting is effective for Asian GC, with new small molecule inhibitors developed.
Area of Science:
- Molecular oncology
- Genomics and transcriptomics
- Cancer therapeutics
Background:
- Gastric cancer (GC) is a heterogeneous disease requiring targeted therapies.
- RHOA (Ras homolog family member A) gene mutations and protein overexpression are implicated in GC, with varying prevalence across ethnicities.
- Precision medicine approaches are needed to address inter-patient variability in GC.
Purpose of the Study:
- To integrate transcriptomic and genomic data for identifying novel therapeutic targets in GC.
- To investigate the role of RHOA signaling in different GC populations.
- To develop evidence-based strategies for biomarker-driven GC therapy.
Main Methods:
- Systematic integration of transcriptomic and genomic data.
- Laboratory validation of predicted signaling subpathways in vitro and in vivo.
- Analysis of RHOA expression patterns, pathway activity, and correlation with RHOB.
- Design strategy for small molecule RHOA inhibitors.
Main Results:
- Identified distinct RHOA expression patterns and pathway activity in Asian versus Caucasian GC tumors.
- Demonstrated that modulating RHOA expression inhibits GC cell growth in vitro and in vivo.
- Observed an inverse correlation between RHOA and RHOB expression.
- Developed a novel small molecule design strategy for RHOA inhibitors.
Conclusions:
- RHOA and its oncogenic signaling pathway are promising biomarker-driven therapeutic targets for Asian GC.
- The study presents a comprehensive strategy for developing targeted cancer therapies.
- The findings support the development of novel 'hit' compounds for GC treatment.
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