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

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.

c‐Met‐dependent phosphorylation of RhoA plays a key role in gastric cancer tumorigenesis

“…Interestingly, a c-Met inhibitor significantly repressed the growth of GC cells transfected with WT-RhoA but not the mutated Y42C form of RhoA. Previously, it was shown that high levels of RhoA increased the activity of Rho GTPases and accelerated the progression of GC [29,30], whilst downregulation of RhoA suppressed GC cell growth [31]. In agreement with previous reports, we found that RhoA is elevated in GC patients and leads to poor survival.…”

SMAD specific E3 ubiquitin protein ligase�1 promotes ovarian cancer cell migration and invasion via the activation of the RhoA/ROCK signaling pathway

“…RhoA, a member of the Rho homolog family of small GTPases, promotes the reorganization of the actin cytoskeleton and regulates cell shape, attachment and motility (26). Increased activation of RhoA has been associated with tumor cell proliferation and metastasis (27,28). In OC, the activation of RhoA GTPase and downstream ROCK led to enhanced cell invasion and migration (29,30).…”

A mutational co-occurrence network in gastric cancer based on an association index

“…Recent GC studies by our group (Chang et al, 2016a;Nam et al, 2014) indicated that WNT5A significantly associated with GC prognosis; we also demonstrated the feasibility of therapeutically targeting WNT signalling (Chang et al, 2016b). In addition, Notch signalling, a well-known cancer hallmark (Hanahan and Weinberg, 2011), also represents a new, promising therapeutic target in GC (Yao et al, 2017), and DNA mutations have been intimately associated with DNA repair pathways (Hanahan and Weinberg, 2011).…”