1. posters
P À 004 Biomarker-directed therapy for invasive Gastric Cancer:
Characterization of a novel regulator of PI3K/AKT/mTOR
signaling
S. Singh, A.P. Kumar
National University of Singapore, Singapore, Singapore
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
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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posters
Annals of Oncology 26 (Supplement 4): iv1–iv100, 2015
doi:10.1093/annonc/mdv233.4
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