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Annual Review of Cancer Biology

Volume 9, 2025

Navigating Nongenetic Plasticity in Cancer Drug Resistance

  • Hanxiao Sun1,2,3, Nitu Kumari1,2,3, Madeline E. Melzer1,2,3, Vadim Backman4 and Yogesh Goyal1,2,3,5
  • 1Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; email: [email protected] 2Center for Synthetic Biology, Northwestern University, Chicago, Illinois, USA 3Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 4Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA 5Chan Zuckerberg Biohub Chicago, LLC, Chicago, Illinois, USA
  • Vol. 9:245-266 (Volume publication date April 2025)
  • First published as a Review in Advance on December 11, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

Nongenetic plasticity has emerged as a key driver of cancer drug resistance, yet its precise origins, nature, and consequences are not fully clarified. This review examines technological, computational, and conceptual developments in the nongenetic determinants of drug resistance. We begin by proposing refined definitions of cellular state, fate, and plasticity. We subsequently contextualize the findings from multimodal approaches to investigate plasticity, highlighting how new single-cell lineage-tracing methods provide opportunities for quantitatively capturing state transitions, their timescales and heritability, and how they contribute to resistance mechanisms. We also draw parallels with concepts from developmental biology and microbial persistence research. Next, we cover the role that computational approaches have played in revealing the otherwise latent patterns of heterogeneity that underlie plasticity from complex datasets. We conclude by emphasizing the need for standardized terminology in this rapidly evolving field and the path from bench to bedside.

Keyword(s): heritability, lineage tracing, nongenetic variability, plasticity, resistance, single cell
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2025-04-11
2025-06-16
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Navigating Nongenetic Plasticity in Cancer Drug Resistance
Annual Review of Cancer Biology 9, 245 (2025); https://doi.org/10.1146/annurev-cancerbio-071924-084617
/content/journals/10.1146/annurev-cancerbio-071924-084617
/content/journals/10.1146/annurev-cancerbio-071924-084617
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