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BOGO: A Proteome-Wide Gene Overexpression Platform for Discovering Rational Cancer Combination Therapies
Kyeong Beom Jo1,2,3, Mohammed M Alruwaili3,4, Da-Eun Kim5
1Surgical and Interventional Sciences, Department of Surgery, McGill University, Montreal, Quebec, Canada.
Abstract:
Cancer drug resistance remains a major barrier to durable treatment success, often leading to relapse despite advances in precision oncology. While combination therapies are being increasingly investigated, such as chemotherapy with small molecule inhibitors, predicting drug response and identifying rational drug combinations based on resistance mechanisms remain major challenges. Therefore, a proteome-wide, single-gene overexpression screening platform is essential for guiding rational therapy selection. Here, we present BOGO (Bxb1-landing pad human ORFeome-integrated system for a proteome-wide Gene Overexpression), a robust, scalable, and reproducible screening platform that enables single-copy, site-specific integration and overexpression of ~19,000 human open across cancer cell models. Using BOGO, we identified drug-specific response drivers for 16 chemotherapeutic agents and integrated clinical datasets to uncover proliferation and resistance-associated genes with prognostic potential. Drug response similarity networks revealed both shared and unique mechanisms, highlighting key pathways such as autophagy, apoptosis, and Wnt signaling, and notable resistance-associated genes including BCL2, POLD2, and TRADD. In particular, we proposed a synergistic combination of the BCL2 family inhibitor ABT-263 (Navitoclax®) and the DNA analog TAS-102 (Lonsurf®), which revealed that lysosomal modulation is a key mechanism driving DNA analog resistance. This combination therapy selectively enhanced cytotoxicity in colorectal and pancreatic cancer cells in vitro, and demonstrated therapeutic benefit in vivo in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Together, these findings establish BOGO as a powerful gene overexpression perturbation platform for systematically identifying chemoresistance and chemosensitization drivers, and for discovering rational combination therapies. Its scalability and reproducibility position BOGO as a broadly applicable tool for functional genomics and therapeutic discovery beyond cancer resistance.
Insights
A new screening platform, BOGO, enables gene overexpression to identify cancer drug resistance mechanisms. This led to a novel combination therapy for colorectal and pancreatic cancers, improving treatment outcomes.
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.
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