P-004 - Biomarker-directed therapy for invasive Gastric Cancer: Characterization of a novel regulator of PI3K/AKT/mTOR signaling

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Gastric Cancer
Translational Research
Presenter S. Singh
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors S. Singh, A.P. Kumar
  • National University of Singapore, Singapore/SG

Abstract

Introduction

Gastric cancer (GC) is the second leading cause of cancer related death worldwide with poor clinical prognosis, limited current treatment options and a “one-size fits all approach”. Dysregulation of the Akt/mTOR pathway is a common event in GC with PIK3CA mutations been reported to correlate with poor prognosis. Although, development of effective dual inhibitors is still premature, dual Akt/mTOR inhibitors are gaining immense interest owing to their advantage of effectively turning off this pathway and overcoming any feedback inhibition normally observed with single inhibitors. Furthermore, prognosis of GC has been far from satisfactory, thus there is an urgent need to identify novel prognostic biomarkers. In this study, we not only discovered a plausible novel role of DP103 in gastric carcinogenesis via its molecular interaction with the PI3K/AKT/mTOR pathway, but also shed light on its novel role in mediating drug resistance in invasive subtypes of GC expressing high levels of this protein.

Methods

Tissue microarray data from two GC cohorts were used in correlation analysis between DP103 and PIK3CA expression (n = 200). Effect of DP103 knockdown on Akt/mTOR pathway was analyzed both in a dose and time dependent manner by western blotting upon drug treatment. DP103's role as a novel regulator was also assessed with DP103 depletion studies and its effect on PI3K/AKT/mTOR pathway proteins by western blotting. Further, DP103 role in drug resistance was examined by FACS analysis of apoptotic death with DP103 depletion and drug treatment.

Results

Our lab recently identified a novel oncogene, DP103, as a mediator of tumor metastasis and drug resistance in breast cancer [PMID: 25083991]. Herein, we provide clinical evidence showing increased expression of DP103 in GC patients' tissues compared to normal gastric tissues (Two sample sets; Discovery n = 47; Validation n = 107). In addition, we show a positive correlation between DP103 and PIK3CA expression in GC patients (n = 200). Through in vitro DP103 knockdown studies done in a high DP103 GC cell line, we showed substantial inhibition of PI3K/AKT/mTOR pathway and its downstream targets important for cell survival following treatment with a dual Akt/mTOR inhibitor. Interestingly, DP103 depletion in gastric cancer cells resulted in a decrease in p70S6K phosphorylation, a kinase downstream of the mTORC1 complex of the Akt/mTOR pathway regulating the IRS-1/p70S6K/mTOR negative feedback loop.

Conclusion

In this study, we not only discovered a plausible novel role of DP103 in gastric carcinogenesis via its molecular interaction with the PI3K/AKT/mTOR signaling pathway, but also shed light on its novel role in mediating drug resistance in invasive GC expressing high levels of this protein. With limited treatment strategies for both, advanced stage GC and drug resistance, targeting novel molecules such as DP103 could be a significant step towards tailored therapy in GC patients with upregulated DP103 expression.

Figure: P-004