RT Journal Article
SR Electronic
T1 USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.17.377705
DO 10.1101/2020.11.17.377705
A1 E. Josue Ruiz
A1 Adan Pinto-Fernandez
A1 Andrew P. Turnbull
A1 Linxiang Lan
A1 Thomas M. Charlton
A1 Hannah Claire Scott
A1 Andreas Damianou
A1 George Vere
A1 Eva M. Riising
A1 Clive Da Costa
A1 Wojciech W. Krajewski
A1 David Guerin
A1 Jeffrey Kearns
A1 Stephanos Ioannidis
A1 Marie Katz
A1 Jonathan C. O’Connell
A1 Natalia Moncaut
A1 Ian Rosewell
A1 Emma Nye
A1 Neil Jones
A1 Claire Heride
A1 Malte Gersch
A1 Min Wu
A1 Christopher J. Dinsmore
A1 Tim R. Hammonds
A1 Sunkyu Kim
A1 David Komander
A1 Sylvie Urbé
A1 Michael J. Clague
A1 Benedikt M. Kessler
A1 Axel Behrens
YR 2020
UL http://biorxiv.org/content/early/2020/11/18/2020.11.17.377705.abstract
AB 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 of USP28 induced regression of established murine LSCC lung tumors. We developed small molecule USP28 inhibitors that inhibit USP28 activity in the low nanomole range. While displaying considerable activity against the closest homologue USP25, these inhibitors 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.Competing Interest StatementThe authors declare competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA.