eLife (Oct 2021)
USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma
- E Josue Ruiz,
- Adan Pinto-Fernandez,
- Andrew P Turnbull,
- Linxiang Lan,
- Thomas M Charlton,
- Hannah C Scott,
- Andreas Damianou,
- George Vere,
- Eva M Riising,
- Clive Da Costa,
- Wojciech W Krajewski,
- David Guerin,
- Jeffrey D Kearns,
- Stephanos Ioannidis,
- Marie Katz,
- Crystal McKinnon,
- Jonathan O'Connell,
- Natalia Moncaut,
- Ian Rosewell,
- Emma Nye,
- Neil Jones,
- Claire Heride,
- Malte Gersch,
- Min Wu,
- Christopher J Dinsmore,
- Tim R Hammonds,
- Sunkyu Kim,
- David Komander,
- Sylvie Urbe,
- Michael J Clague,
- Benedikt M Kessler,
- Axel Behrens
Affiliations
- E Josue Ruiz
- Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom
- Adan Pinto-Fernandez
- ORCiD
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Andrew P Turnbull
- London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom
- Linxiang Lan
- Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom
- Thomas M Charlton
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Hannah C Scott
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Andreas Damianou
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- George Vere
- ORCiD
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Eva M Riising
- Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom
- Clive Da Costa
- Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom
- Wojciech W Krajewski
- London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom
- David Guerin
- FORMA Therapeutics, Watertown, United Kingdom
- Jeffrey D Kearns
- ORCiD
- FORMA Therapeutics, Watertown, United Kingdom
- Stephanos Ioannidis
- FORMA Therapeutics, Watertown, United Kingdom
- Marie Katz
- FORMA Therapeutics, Watertown, United Kingdom
- Crystal McKinnon
- FORMA Therapeutics, Watertown, United Kingdom
- Jonathan O'Connell
- FORMA Therapeutics, Watertown, United Kingdom
- Natalia Moncaut
- Genetic Manipulation Service, The Francis Crick Institute, London, United States
- Ian Rosewell
- Genetic Manipulation Service, The Francis Crick Institute, London, United States
- Emma Nye
- Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom
- Neil Jones
- London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom
- Claire Heride
- ORCiD
- London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom
- Malte Gersch
- Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Min Wu
- FORMA Therapeutics, Watertown, United Kingdom
- Christopher J Dinsmore
- FORMA Therapeutics, Watertown, United Kingdom
- Tim R Hammonds
- London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom
- Sunkyu Kim
- Incyte, Wilmington, United States
- David Komander
- Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Royal Parade, and Department of Medical Biology, University of Melbourne, Melbourne, Australia
- Sylvie Urbe
- Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
- Michael J Clague
- ORCiD
- Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
- Benedikt M Kessler
- ORCiD
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Axel Behrens
- ORCiD
- Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom; Cancer Stem Cell Laboratory, Institute of Cancer Research, London, United Kingdom; Imperial College, Division of Cancer, Department of Surgery and Cancer, London, United Kingdom; Convergence Science Centre, Imperial College, London, United Kingdom
- DOI
- https://doi.org/10.7554/eLife.71596
- Journal volume & issue
-
Vol. 10
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
