Development of a cell-based pathway modulator screening system to screen the targeted cancer therapeutic candidates.

Abstract

To overcome the issues of poor prognosis and to tackle the non-responsiveness to various chemotherapeutics; it is necessary to develop targeted cancer therapeutic agents. Also, it is being necessary to understand the molecular targets of the drug candidates and drugs in the context of cellular signaling pathways, to make progress towards the development of targeted cancer therapeutics. Towards addressing these, we have established a cell-based and pathway-focused drug screening system for the pathways such as MYC, E2F, WNT, ERK, NRF1/2, HIF1α, p53, YY1 and NFκB. These signaling pathways are highly dysregulated in many cancers, including gastric cancer. The developed firefly luciferase assay-based screening system in gastric cancer lineage is suitable for the screening of the massive panel of drugs, drug candidates, small molecule inhibitors, chemicals and alternate drug formulations. The developed stable cell lines have been demonstrated for their pathway activity reporting features using the corresponding pathway-specific modulators. A proof-of-concept medium throughput screening focusing on YY1 signaling pathway also revealed the connection between calcium channel blockers and YY1 signaling. The developed signaling pathway screening assay cells are valuable resource and will serve as the screening platform for screening the drug libraries towards the development of targeted cancer therapeutics.