Gene context drift identifies drug targets to mitigate cancer treatment resistance

Amir Jassim¹, Birgit V Nimmervoll², Sabrina Terranova², Erica Nathan², Linda Hu², Jessica T Taylor², Katherine E Masih³, Lisa Ruff², Matilde Duarte², Elizabeth Cooper², Gunjan Katyal², Melika Akhbari², Reuben J Gilbertson², Jennifer C Coleman², Joseph S Toker², Colton Terhune², Gabriel Balmus⁴, Stephen P Jackson², Hailong Liu⁵, Tao Jiang⁶, Michael D Taylor⁷, Kui Hua², Jean E Abraham⁸, Mariella G Filbin⁹, Anthony Hill¹⁰, Anarita Patrizi¹⁰, Neil Dani¹¹, Aviv Regev¹², Maria K Lehtinen⁹, Richard J Gilbertson¹³

Affiliations

¹ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. Electronic address: amir.jassim@cruk.cam.ac.uk.
² Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
³ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethseda, MD 20892, USA.
⁴ UK Dementia Research Institute at the University of Cambridge and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK; Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, 400191 Cluj-Napoca, Romania.
⁵ Department of Radiotherapy, Beijing Tiantan Hospital Capital Medical University, Beijing 100070, China.
⁶ Department of Pediatric Neurosurgery, Beijing Tiantan Hospital Capital Medical University, Beijing 100070, China.
⁷ Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁸ Department of Oncology, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; Precision Breast Cancer Institute, Box 197 Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
⁹ Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
¹⁰ Schaller Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
¹¹ Department of Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, TN 37232, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK. Electronic address: richard.gilbertson@cruk.cam.ac.uk.

PMID: 40578362
DOI: 10.1016/j.ccell.2025.06.005

Gene context drift identifies drug targets to mitigate cancer treatment resistance

Amir Jassim et al. Cancer Cell. 2025.

. 2025 Sep 8;43(9):1608-1621.e9.

doi: 10.1016/j.ccell.2025.06.005. Epub 2025 Jun 26.

Authors

Affiliations

¹ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. Electronic address: amir.jassim@cruk.cam.ac.uk.
² Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
³ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethseda, MD 20892, USA.
⁴ UK Dementia Research Institute at the University of Cambridge and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK; Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, 400191 Cluj-Napoca, Romania.
⁵ Department of Radiotherapy, Beijing Tiantan Hospital Capital Medical University, Beijing 100070, China.
⁶ Department of Pediatric Neurosurgery, Beijing Tiantan Hospital Capital Medical University, Beijing 100070, China.
⁷ Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁸ Department of Oncology, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; Precision Breast Cancer Institute, Box 197 Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
⁹ Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
¹⁰ Schaller Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
¹¹ Department of Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, TN 37232, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK. Electronic address: richard.gilbertson@cruk.cam.ac.uk.

PMID: 40578362
DOI: 10.1016/j.ccell.2025.06.005

Abstract

Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments for mice with choroid plexus carcinoma, and the prediction of potential new treatments for patients with medulloblastoma and triple-negative breast cancer. Thus, RECODR may unravel the complexity of cancer treatment resistance by detecting context-specific changes in gene interactions that determine the resistant phenotype.

Keywords: DNA repair; cancer; choroid plexus; choroid plexus carcinoma; combination therapy; graph networks; machine learning; radiation; treatment resistance; triple-negative breast cancer.

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Conflict of interest statement

Declaration of interests Richard J. Gilbertson is a paid consultant of AstraZeneca serving on their Pediatric Cancer Advisory Board. All other authors declare no competing interest.

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Gene context drift identifies drug targets to mitigate cancer treatment resistance

Affiliations

Gene context drift identifies drug targets to mitigate cancer treatment resistance

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms