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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancer treatment faces challenges due to poor prognosis and drug resistance.
• Understanding molecular targets within cellular signaling pathways is vital for developing effective cancer therapeutics.
• Several key signaling pathways (MYC, E2F, WNT, ERK, NRF1/2, HIF1α, p53, YY1, NFκB) are frequently dysregulated in various cancers, including gastric cancer.

Purpose of the Study:

• To establish a cell-based, pathway-focused drug screening system for identifying novel cancer therapeutic agents.
• To enable the screening of extensive drug libraries and candidates targeting cancer-related signaling pathways.
• To provide a platform for advancing targeted cancer therapy development.

Main Methods:

• Development of a firefly luciferase assay-based screening system using gastric cancer cell lines.
• Creation of stable cell lines engineered to report activity in specific signaling pathways.
• Utilized pathway-specific modulators to validate the cell lines' reporting capabilities.
• Conducted a proof-of-concept medium-throughput screen targeting the YY1 signaling pathway.

Main Results:

• Successfully established a versatile screening system for evaluating drugs, drug candidates, small molecules, and alternative formulations.
• Demonstrated the functionality of the developed stable cell lines in accurately reporting pathway activity.
• A pilot screen identified a potential link between calcium channel blockers and the YY1 signaling pathway.

Conclusions:

• The developed cell-based screening platform is a valuable resource for accelerating the discovery of targeted cancer therapeutics.
• This system facilitates the screening of large compound libraries against critical cancer signaling pathways.
• The findings support the potential of targeting specific pathways for improved cancer treatment strategies.