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ResearchIn-Press PreviewCell biologyGeneticsOncology Open Access | 10.1172/JCI202898

Combined inhibition of DNA Polymerase Theta and ATR targets MYBL2-high triple-negative breast cancer stem cells

Rachel Bayley,1 Xiaoping Qu,1 Adrija Chakraborty,1 Menna Shamma,1 Ciara Ward,1 Kinga Koscielniak,1 Anna Munsey,1 Suman Ahmed,1 Amber Stiby,1 Bohdana-Myroslava Briantseva,1 Kirendeep Jawanda,1 Christopher J. Lord,2 Abeer M. Shaaban,1 Marco Saponaro,1 Graeme C. M. Smith,3 Robert B. Clarke,4 Clare Davies,1 and Paloma Garcia1

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Bayley, R. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

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1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Chakraborty, A. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

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1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Ward, C. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Koscielniak, K. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

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1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

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1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Stiby, A. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Briantseva, B. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Jawanda, K. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Lord, C. in: PubMed | Google Scholar |

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Shaaban, A. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Saponaro, M. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Smith, G. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Clarke, R. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Davies, C. in: PubMed | Google Scholar

1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom

2Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom

3ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom

4Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Find articles by Garcia, P. in: PubMed | Google Scholar

Published October 13, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI202898.
Copyright © 2026, Bayley et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 13, 2026 - Version history
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Abstract

Triple negaJve breast cancer (TNBC) is characterised by poor prognosis and limited treatment opJons, parJally due to therapy-resistant stem/progenitor cells driving metastasis. Elevated expression of the transcripJon factor MYBL2 is associated with aggressive disease, yet its role in BC stem/progenitor cells remains elusive. Here, we employed inducible MYBL2 downregulaJon in TNBC cell lines and paJent-derived models to invesJgate its funcJon and idenJfy potenJal vulnerabiliJes associated with its high expression. Our funcJonal and mechanisJc analyses reveal that high MYBL2 levels are criJcal for stem cell self-renewal, DNA repair, and replicaJon stress response and lowering MYBL2 impairs stemness and self-renewal both in vitro and in vivo. Accordingly, high-MYBL2 stem/progenitor cells exhibit increased sensiJvity to Polθ inhibitors which is lost upon MYBL2 downregulaJon due to transcripJonal suppression. Combining Polθ inhibitors with ATR inhibitors further enhances this sensiJvity, in vitro, ex vivo and in vivo. These findings suggest that dual Polθ/ATR inhibiJon represents a promising therapeuJc strategy to target TNBC stem/progenitor cells with high MYBL2 expression, highlighJng MYBL2 as a potenJal biomarker to straJfy paJents for Polθ inhibitor-based therapies in TNBC.

Graphical Abstract
graphical abstract
Supplemental material

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Version history
  • Version 1 (October 13, 2026): In-Press Preview
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