USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma

  • Elife. 2021 Oct 12:10:e71596. doi: 10.7554/eLife.71596.
E Josue Ruiz  1 ,  Adan Pinto-Fernandez  2 ,  Andrew P Turnbull  3 ,  Linxiang Lan  1 ,  Thomas M Charlton  2 ,  Hannah C Scott  2 ,  Andreas Damianou  2 ,  George Vere  2 ,  Eva M Riising  1 ,  Clive Da Costa  1 ,  Wojciech W Krajewski  3 ,  David Guerin  4 ,  Jeffrey D Kearns  4 ,  Stephanos Ioannidis  4 ,  Marie Katz  4 ,  Crystal McKinnon  4 ,  Jonathan O'Connell  4 ,  Natalia Moncaut  5 ,  Ian Rosewell  5 ,  Emma Nye  1 ,  Neil Jones  3 ,  Claire Heride  3 ,  Malte Gersch  6 ,  Min Wu  4 ,  Christopher J Dinsmore  4 ,  Tim R Hammonds  3 ,  Sunkyu Kim  7 ,  David Komander  8 ,  Sylvie Urbe  9 ,  Michael J Clague  9 ,  Benedikt M Kessler  2 ,  Axel Behrens  1  10  11  12
Affiliations
  • 1. Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom.
  • 2. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • 3. London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom.
  • 4. FORMA Therapeutics, Watertown, United Kingdom.
  • 5. Genetic Manipulation Service, The Francis Crick Institute, London, United States.
  • 6. Max Planck Institute of Molecular Physiology, Dortmund, Germany.
  • 7. Incyte, Wilmington, United States.
  • 8. Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Royal Parade, and Department of Medical Biology, University of Melbourne, Melbourne, Australia.
  • 9. Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
  • 10. Cancer Stem Cell Laboratory, Institute of Cancer Research, London, United Kingdom.
  • 11. Imperial College, Division of Cancer, Department of Surgery and Cancer, London, United Kingdom.
  • 12. Convergence Science Centre, Imperial College, London, United Kingdom.
PMID: 34636321 DOI: 10.7554/eLife.71596
Abstract

Lung Squamous Cell Carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient's 5-year survival rate is less than 5%. The Ubiquitin-Specific Protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-Myc, c-Jun, and Δp63. Here, we show that genetic inactivation of USP28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 Inhibitor treatment resulted in a dramatic decrease in c-Myc, c-Jun, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.

Keywords
USP28; biochemistry; c-MYC; cancer biology; chemical biology; human; squamous cell lung cancer.
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