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

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

  • bioRxiv. 2025 Sep 7:2025.09.02.673780. doi: 10.1101/2025.09.02.673780.
Kyeong Beom Jo 1 2 3,  Mohammed M Alruwaili 3,  Da-Eun Kim 4,  Yongjun Koh 5,  Hyeyeon Kim 2,  Kwontae You 6,  Ji-Sun Kim 2,  Saba Sane 1 2,  Yanqi Guo 3,  Jacob P Wright 3,  Hyobin Julianne Lim 3 7,  Maricris N Naranjo 3,  Atina G Coté 8,  Frederick P Roth 9,  David E Hill 10 11 12,  Jung-Hyun Choi 13,  Hunsang Lee 14,  Kenneth A Matreyek 15,  Kyle K-H Farh 6,  Jong-Eun Park 5,  Hyunkyung Kim 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18,  Andrei V Bakin 3,  Dae-Kyum Kim 1 2 3 16 17 18
Affiliations

Affiliations

  • 1 Division of Surgical and Interventional Sciences, Department of Surgery, McGill University, Montreal, Quebec, Canada.
  • 2 Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
  • 3 Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
  • 4 Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
  • 5 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
  • 6 Illumina Artificial Intelligence Laboratory, Illumina Inc., San Diego, California, USA.
  • 7 Tetrad Graduate Program, University of California, San Francisco, California, USA.
  • 8 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
  • 9 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, USA.
  • 10 Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 11 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 12 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 13 Department of Biochemistry, Chungbuk National University, Cheongju, Korea.
  • 14 Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
  • 15 Department of Pathology, School of Medicine, Case Western Reverse University, Cleveland, Ohio, USA.
  • 16 Division of Thoracic and Upper Gastrointestinal Surgery, Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada.
  • 17 Montreal General Hospital Foundation, McGill University Health Centre, Montreal, Quebec, Canada.
  • 18 Aune Foundation, Vancouver, British Columbia, Canada.
PMID: 40950237 DOI: 10.1101/2025.09.02.673780
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 ORFs 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.

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