Institut za onkologiju i radiologiju Srbije / Institute for Oncology and Radiology of Serbia
Published January 28, 2021 | Version v.1
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3D functional genomics screens identify CREBBP as a targetable driver in aggressive triple-negative breast cancer

Authors/Creators

  • 1. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK 2Division of Molecular Pathology, The Institute of Cancer Research, London
  • 2. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
  • 3. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK 3Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
  • 4. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK 4Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
  • 5. Division of Cancer Biology, The Institute of Cancer Research, London, UK
  • 6. Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester
  • 7. SGC Oxford. University of Oxford, Old Road Campus Research Building Roosevelt Drive Headington Oxford, UK
  • 8. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK; Breast Cancer Now Research Unit, King's College London, London, UK
  • 9. The Royal Marsden NHS Foundation Trust, London, UK
  • 10. Department of Medical Oncology, The Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
  • 11. Department of Pathology and Cytology, The Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
  • 12. Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK
  • 13. Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; UMR981, ATIP-Avenir team, INSERM, Villejuif, France
  • 14. Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
  • 15. Division of Molecular Pathology, The Institute of Cancer Research, London
  • 16. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK; Breast Cancer Now Research Unit, King's College London, London, UK

Description

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model in vivo–like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population.

Significance: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.

Notes

This work was funded by Programme Grants from Breast Cancer Now as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre (B Peck, P Bland, G Muirhead, SL Maguire, D Kriplani, A Gibson, R Marlow, R Buus, D Novo, E Knight, N Guppy, P Gazinska, I Roxanis, LA Martin, EM Holgersen, F Noor, F Daley, F Wallberg, S Haider, AN Tutt, R Natrajan)...

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Additional details

Related works

Is identical to
PMC7611219 (pmcid)
Is supplemented by
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611219/#SMtitle (URL)