Abstract 5596: Identification of relapse prediction marker for advanced gastric cancer using reverse-phase protein arrays
Authors: Satoshi S. Nishizuka, Fumitaka Endo, Kazushige Ishida, Hirokatsu Katagiri, Kei Sato, Kohei Kume, Kaoru Ishida, Takeshi Iwaya, Keisuke Koeda, Go Wakabayashi
Journal: Cancer Research (2014)

Abstract While post-operative adjuvant chemotherapy regimens have been established in various cancers, a considerable number of patients experience recurrence despite of these therapies. To examine whether any protein expression at the time of operation can predict the relapse, we screened for anticancer-associated proteins using clinically approved drugs and a panel of human cancer cell lines. A Cell x Protein matric (CP matric) was generated using reverse-phase protein arrays (RPPAs), which was then combined with a Cell x (drug) Activity matric (CA matric) defined by 50% growth suppression concentration of each drug. For the validation of post-operative adjuvant chemotherapy model, we used archived human gastric cancer specimens that have been removed by curative surgery and that all patients received 5-FU-based post-operative adjuvant chemotherapy. Proteomic and drug activity profiling revealed that 10 candidate proteins that have been highly correlated with 5-FU sensitivity. Among the candidates, NF-κB and JNK proteins were finally identified as the most correlated biomarkers from immunohistochemical confirmation using a total of 79 gastrointestinal cancer specimens. A comparison of NF-κB(+) and JNK(-) pattern demonstrated a strong power distinguishing non-relapsed from relapsed gastric cancers [NF-κB(+), p = 0.0002, HR11.7; JNK(-), p = 0.0302. HR4.4]. Subsequent analysis of RELA gene, one of the NF-κB component coding genes, knockdown demonstrated that the reduction of 5-FU resistance in three out of 5 human gastric cancer cell lines. Further studies of NF-κB transcriptional activity to 5-FU indicated that NF-κB incorporates p53 as a part of DNA damaging response. In fact, a polymorphic site in codon 72 of TP53 gene, which is important for NF-κB binding, showed a strong correlation with 5-FU sensitivity in nine gastric cancer cell lines. Gastric cancer cell lines bearing Pro/Pro homozigosity (n = 5) in codon 72 are more resistant to 5-FU than those with Arg/Arg homozigosity (n = 3). Based on these results, we have started a nationwide clinical study “Predictive Biomarkers in Stage II/III Gastric Cancer for Adjuvant Chemotherapy (NJ Biomarker study, NCT01905969)” for examining clinical utility of NF-κB/JNK in the context of gastric cancer adjuvant chemotherapy. An estimate of potential patients for this post-operative/pre-chemotherapy screening would be at least 2 million worldwide. Citation Format: Satoshi S. Nishizuka, Fumitaka Endo, Kazushige Ishida, Hirokatsu Katagiri, Kei Sato, Kohei Kume, Kaoru Ishida, Takeshi Iwaya, Keisuke Koeda, Go Wakabayashi. Identification of relapse prediction marker for advanced gastric cancer using reverse-phase protein arrays. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5596. doi:10.1158/1538-7445.AM2014-5596