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 language | English |
|---|---|
| Pages (from-to) | 81435-81451 |
| Number of pages | 17 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 49 |
| DOIs | |
| Publication status | Published - 2016 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Oncology
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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 journal › Article
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85000936702&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85000936702&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.12963
DO - 10.18632/oncotarget.12963
M3 - Article
C2 - 27806312
AN - SCOPUS:85000936702
VL - 7
SP - 81435
EP - 81451
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 49
ER -