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, Yon Hui Kim

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)81435-81451
Number of pages17
JournalOncotarget
Volume7
Issue number49
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

Stomach Neoplasms
Biomarkers
Neoplasms
Therapeutics
Precision Medicine
Mutation
Monomeric GTP-Binding Proteins
Evidence-Based Medicine
Tumor Biomarkers
Genome
Cell Line
Growth
Population
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Chang, H. R., Nam, S., Lee, J., Kim, J. H., Jung, H. R., Park, H. S., ... Kim, Y. H. (2016). Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer. Oncotarget, 7(49), 81435-81451. https://doi.org/10.18632/oncotarget.12963
Chang, Hae Ryung ; Nam, Seungyoon ; Lee, Jinhyuk ; Kim, Jin Hee ; Jung, Hae Rim ; Park, Hee Seo ; Park, Sungjin ; Ahn, Young Zoo ; Huh, Iksoo ; Balch, Curt ; Ku, Ja Lok ; Powis, Garth ; Park, Taesung ; Jeong, Jin-Hyun ; Kim, Yon Hui. / Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer. In: Oncotarget. 2016 ; Vol. 7, No. 49. pp. 81435-81451.
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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.",
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Chang, HR, Nam, S, Lee, J, Kim, JH, Jung, HR, Park, HS, Park, S, Ahn, YZ, Huh, I, Balch, C, Ku, JL, Powis, G, Park, T, Jeong, J-H & Kim, YH 2016, 'Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer', Oncotarget, vol. 7, no. 49, pp. 81435-81451. https://doi.org/10.18632/oncotarget.12963

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer. / Chang, Hae Ryung; Nam, Seungyoon; Lee, Jinhyuk; Kim, Jin Hee; Jung, Hae Rim; Park, Hee Seo; Park, Sungjin; Ahn, Young Zoo; Huh, Iksoo; Balch, Curt; Ku, Ja Lok; Powis, Garth; Park, Taesung; Jeong, Jin-Hyun; Kim, Yon Hui.

In: Oncotarget, Vol. 7, No. 49, 01.01.2016, p. 81435-81451.

Research output: Contribution to journalArticle

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T1 - Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

AU - Chang, Hae Ryung

AU - Nam, Seungyoon

AU - Lee, Jinhyuk

AU - Kim, Jin Hee

AU - Jung, Hae Rim

AU - Park, Hee Seo

AU - Park, Sungjin

AU - Ahn, Young Zoo

AU - Huh, Iksoo

AU - Balch, Curt

AU - Ku, Ja Lok

AU - Powis, Garth

AU - Park, Taesung

AU - Jeong, Jin-Hyun

AU - Kim, Yon Hui

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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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