BOGO: A Proteome-Wide Gene Overexpression Platform for Discovering Rational Cancer Combination Therapies

Area of Science:

• Genomics and Proteomics
• Cancer Biology
• Drug Discovery

Background:

• Cancer drug resistance is a major obstacle to successful treatment, hindering precision oncology.
• Predicting drug response and identifying effective combination therapies based on resistance mechanisms are significant challenges.
• A proteome-wide, single-gene overexpression screening platform is crucial for guiding rational therapeutic strategies.

Purpose of the Study:

• To develop and validate BOGO (Bxb1-landing pad human ORFeome-integrated system for a proteome-wide Gene Overexpression), a scalable platform for single-gene overexpression screening.
• To identify drug-specific response drivers and prognostic genes associated with cancer proliferation and resistance.
• To discover novel, rational combination therapies by understanding chemoresistance and chemosensitization mechanisms.

Main Methods:

• Developed BOGO, a robust platform for site-specific integration and overexpression of ~19,000 human genes in cancer cell models.
• Performed proteome-wide overexpression screens to identify drug response drivers for 16 chemotherapeutic agents.
• Integrated clinical datasets and analyzed drug response similarity networks to uncover resistance pathways and genes.
• Proposed and tested a combination therapy of a BCL2 inhibitor (ABT-263) and a DNA analog (TAS-102).

Main Results:

• Identified drug-specific response drivers and prognostic genes linked to proliferation and resistance.
• Uncovered shared and unique resistance mechanisms, highlighting pathways like autophagy, apoptosis, and Wnt signaling.
• Discovered that lysosomal modulation is key to DNA analog resistance, with BCL2, POLD2, and TRADD being notable resistance genes.
• Demonstrated synergistic cytotoxicity of ABT-263 and TAS-102 in colorectal and pancreatic cancer cells in vitro and therapeutic benefit in vivo in CDX and PDX models.

Conclusions:

• BOGO is a powerful platform for systematically identifying drivers of chemoresistance and chemosensitization.
• The study identified a novel synergistic combination therapy with potential for treating colorectal and pancreatic cancers.
• BOGO's scalability and reproducibility make it a valuable tool for functional genomics and therapeutic discovery beyond cancer resistance.