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.
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Change history
13 June 2025
In the version of the article initially published, the Fig. 1 legend inadvertently omitted to state that the figure is adapted from Laisné, M., Lupien, M. & Vallot, C. Epigenomic heterogeneity as a source of tumour evolution. Nat. Rev. Cancer 25, 7–26 (2025). This has now been corrected in the HTML and PDF versions of the article.
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Acknowledgements
The authors thank M. Espey and J. Hildesheim for helpful discussions. They acknowledge the following grant support: R01CA244729 and R01CA244729-03S (to A.S. and P.C.B.); R01CA240718 and R01CA264248 (to A.S.); P30CA016042, U2CCA271894, U24CA248265 and DOD W81XWH2210751 (to P.C.B.); U01CA223976 and U01CA223976-03S1 (to C.D.W.); R01CA247362 and R01CA267467 (to E.S.K. and A.K.W.); U24CA274159, R01CA234162 and PCF 22CHAL13 (to D.W.G.); U54CA274220 (to D.J. and S.T.G.); U54CA224019 (to C.E.T. and J.W.T.); U01CA271412 (to C.E.T.); U54CA224081 (to T.G.B.); R01CA175495 (to X.Z.); U54CA274321 (to V.C.S., A.A.O. and J.N.M.); R01CA280980 (to V.C.S.); R01CA270234, R01CA163649, R01CA256911 and U54CA274329 (to P.K.S.); R37CA276924 (to K.M.); and R01CA175397-07S1 (to K.S.C.).
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E.S.K., T.N.O., A.K.W. and A.S. researched data for the article. E.S.K., T.N.O., C.E.T., J.W.T., B.G., T.G.B., D.W.G., P.K.S., K.S.C., H.M. and A.S. contributed substantially to discussion of the content. E.S.K., C.E.T., J.W.T., B.G., T.G.B., X.Z., A.K.W., D.W.G., D.J., S.T.G., C.D.W., P.C.B., V.C.S., A.A.O., J.N.M., P.K.S., D.K., K.S.C. and A.S. wrote the article. E.S.K., T.N.O., B.G., T.G.B., X.Z., C.D.W., V.C.S., A.A.O. and A.S. reviewed and/or edited the manuscript before submission.
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The authors declare no direct competing interests. For full disclosure, C.D.W. has received research funding from Varian Medical Systems, AACR-Novocure and OMS Foundation, clinical trial support from MuReva and Tactile Medical, and consultancy/honoraria from LifeNet Health, Guidepoint Global and EMD Serono; A.S. sits on the Board of the Society for Functional Precision Medicine; P.C.B. sits on the Scientific Advisory Boards of Intersect Diagnostics Inc., BioSymetrics Inc. and previously sat on the board of Sage Bionetworks; E.S.K. has sponsored research funded by Blueprint Medicines and Bristol Myers Squibb and is a member of the Cancer Cell Cyclse–LLC consulting enterprise; A.K.W. has sponsored research funded by Blueprint Medicines and Bristol Myers Squibb; C.E.T. has received funding from AstraZeneca; J.W.T. has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda and Tolero and serves on the advisory board for Recludix Pharm, AmMax Bio and Ellipses Pharma; V.C.S. is a consultant for and equity holder in Femtovox Inc.
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Soragni, A., Knudsen, E.S., O’Connor, T.N. et al. Acquired resistance in cancer: towards targeted therapeutic strategies. Nat Rev Cancer 25, 613–633 (2025). https://doi.org/10.1038/s41568-025-00824-9
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DOI: https://doi.org/10.1038/s41568-025-00824-9
