2. Academic Validation
  3. USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138698
    98.40%, Ubiquitin-Specific Protrase Inhibitor