USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma

  1. E. Josue Ruiz
  2. Adan Pinto-Fernandez
  3. Andrew P. Turnbull
  4. Linxiang Lan
  5. Thomas M. Charlton
  6. Hannah Claire Scott
  7. Andreas Damianou
  8. George Vere
  9. Eva M. Riising
  10. Clive Da Costa
  11. Wojciech W. Krajewski
  12. David Guerin
  13. Jeffrey Kearns
  14. Stephanos Ioannidis
  15. Marie Katz
  16. Crystal McKinnon
  17. Jonathan C. O’Connell
  18. Natalia Moncaut
  19. Ian Rosewell
  20. Emma Nye
  21. Neil Jones
  22. Claire Heride
  23. Malte Gersch
  24. Min Wu
  25. Christopher J. Dinsmore
  26. Tim R. Hammonds
  27. Sunkyu Kim
  28. David Komander
  29. Sylvie Urbé
  30. Michael J. Clague
  31. Benedikt M. Kessler
  32. Axel Behrens
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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 oncoprotein c-MYC. Here, we show that genetic inactivation ofUsp28induced regression of established murine LSCC lung tumors. 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 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.

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