USP28 deletion and small molecule inhibition destabilises c-MYC and elicits regression of squamous cell lung carcinoma
- The Francis Crick Institute, United Kingdom
- University of Oxford, United Kingdom
- CRUK Therapeutic Discovery Laboratories, United Kingdom
- Forma Therapeutics, United States
- Novartis Institutes of BioMedical Research, United States
- FORMA Therapeutics, United States
- University College London, United Kingdom
- Francis Crick Institute, United Kingdom
- Max Planck Institut, Dortmund, Germany
- Walter and Eliza Hall Institute of Medical Research, Australia
- Liverpool University, United Kingdom
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 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoproteins c-MYC, c-JUN and Dp63. 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 Dp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors 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.
Data availability
For all figures with graphs we provide source data files in the Supplemental Information section. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with an internal ID of PXD469830.
Article and author information
Author details
Benedikt M Kessler
Funding
Forma Therapeutics (2013-2019)
- 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
Cancer Research UK Manchester Centre (FC001039)
- Axel Behrens
Medical Research Council (FC001039)
- Axel Behrens
Wellcome Trust (FC001039)
- Axel Behrens
Wellcome Trust (097813/Z/11/Z)
- Benedikt M Kessler
Engineering and Physical Sciences Research Council (EP/N034295/1)
- Benedikt M Kessler
John Fell Fund, University of Oxford (133/075)
- Benedikt M Kessler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by the Francis Crick Institute Animal Ethics Committee and conformed to UK Home Office regulations under the Animals (Scientific Procedures) Act 1986 including Amendment Regulations 2012.
Copyright
© 2021, Ruiz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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USP28 deletion and small molecule inhibition destabilises c-MYC and elicits regression of squamous cell lung carcinoma
eLife 10:e71596.
https://doi.org/10.7554/eLife.71596
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