TY - JOUR T1 - USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma JF - bioRxiv DO - 10.1101/2020.11.17.377705 SP - 2020.11.17.377705 AU - E. Josue Ruiz AU - Adan Pinto-Fernandez AU - Andrew P. Turnbull AU - Linxiang Lan AU - Thomas M. Charlton AU - Hannah Claire Scott AU - Andreas Damianou AU - George Vere AU - Eva M. Riising AU - Clive Da Costa AU - Wojciech W. Krajewski AU - David Guerin AU - Jeffrey Kearns AU - Stephanos Ioannidis AU - Marie Katz AU - Jonathan C. O’Connell AU - Natalia Moncaut AU - Ian Rosewell AU - Emma Nye AU - Neil Jones AU - Claire Heride AU - Malte Gersch AU - Christopher J. Dinsmore AU - Tim R. Hammonds AU - Sunkyu Kim AU - David Komander AU - Sylvie Urbé AU - Michael J. Clague AU - Benedikt M. Kessler AU - Axel Behrens Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/17/2020.11.17.377705.abstract N2 - 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. ER -