Acquired resistance in cancer: towards targeted therapeutic strategies.

Journal: Nature reviews. Cancer
Published Date: Jun 3, 2025

Abstract

Development of acquired therapeutic resistance limits the efficacy of cancer treatments and accounts for therapeutic failure in most patients. How resistance arises, varies across cancer types and differs depending on therapeutic modalities is incompletely understood. Novel strategies that address and overcome the various and complex resistance mechanisms necessitate a deep understanding of the underlying dynamics. We are at a crucial time when innovative technologies applied to patient-relevant tumour models have the potential to bridge the gap between fundamental research into mechanisms and timing of acquired resistance and clinical applications that translate these findings into actionable strategies to extend therapy efficacy. Unprecedented spatial and time-resolved high-throughput platforms generate vast amounts of data, from which increasingly complex information can be extracted and analysed through artificial intelligence and machine learning-based approaches. This Roadmap outlines key mechanisms that underlie the acquisition of therapeutic resistance in cancer and explores diverse modelling strategies. Clinically relevant, tractable models of disease and biomarker-driven precision approaches are poised to transform the landscape of acquired therapy resistance in cancer and its clinical management. Here, we propose an integrated strategy that leverages next-generation technologies to dissect the complexities of therapy resistance, shifting the paradigm from reactive management to predictive and proactive prevention.

Authors

  • Alice Soragni
    Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA, USA. alices@mednet.ucla.edu.
  • Erik S Knudsen
    Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Street, Buffalo, NY, 14263, USA. erik.knudsen@roswellpark.org.
  • Thomas N O'Connor
    Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Street, Buffalo, NY, 14263, USA.
  • Cristina E Tognon
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • Jeffrey W Tyner
    Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • Beatrice Gini
    Department of Medicine, University of California at San Francisco, San Francisco, CA, USA.
  • Donghwa Kim
    Department of Medicine, University of California at San Francisco, San Francisco, CA, USA.
  • Trever G Bivona
    Department of Medicine, University of California at San Francisco, San Francisco, CA, USA.
  • Xingxing Zang
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Agnieszka K Witkiewicz
    Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Street, Buffalo, NY, 14263, USA. agnieszka.witkiewicz@roswellpark.org.
  • David W Goodrich
    Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Dadi Jiang
    Department of Radiation Oncology, Stanford University School of Medicine , Stanford, California 94305, United States.
  • Seth T Gammon
    Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Christopher D Willey
    Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Paul C Boutros
    Ontario Institute of Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Human Genetics, University of California, Los Angeles, CA 90095, USA; Department of Urology, University of California, Los Angeles, CA 90095, USA; Institute for Precision Health, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
  • Vlad C Sandulache
    Bobby R. Alford Department of Otolaryngology, Baylor College of Medicine, Houston, TX, USA.
  • Abdullah A Osman
    Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Jeffrey N Myers
    Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • Kamiya Mehla
    Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • Pankaj K Singh
    Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
  • Keith S Chan
    Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
  • Hongbo Gao
    Department of Radiation Oncology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China.
  • Himangi Marathe
    Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

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