PMID- 34636321 OWN - NLM STAT- MEDLINE DCOM- 20211124 LR - 20220218 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 10 DP - 2021 Oct 12 TI - USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma. LID - 10.7554/eLife.71596 [doi] LID - e71596 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'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 Deltap63. 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 Deltap63 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. CI - (c) 2021, Ruiz et al. FAU - Ruiz, E Josue AU - Ruiz EJ AD - Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom. FAU - Pinto-Fernandez, Adan AU - Pinto-Fernandez A AUID- ORCID: 0000-0003-1693-9664 AD - Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Turnbull, Andrew P AU - Turnbull AP AD - London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom. FAU - Lan, Linxiang AU - Lan L AD - Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom. FAU - Charlton, Thomas M AU - Charlton TM AD - Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Scott, Hannah C AU - Scott HC AD - Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Damianou, Andreas AU - Damianou A AD - Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Vere, George AU - Vere G AUID- ORCID: 0000-0002-1154-5212 AD - Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Riising, Eva M AU - Riising EM AD - Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom. FAU - Da Costa, Clive AU - Da Costa C AD - Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom. FAU - Krajewski, Wojciech W AU - Krajewski WW AD - London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom. FAU - Guerin, David AU - Guerin D AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - Kearns, Jeffrey D AU - Kearns JD AUID- ORCID: 0000-0001-7261-5096 AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - Ioannidis, Stephanos AU - Ioannidis S AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - Katz, Marie AU - Katz M AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - McKinnon, Crystal AU - McKinnon C AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - O'Connell, Jonathan AU - O'Connell J AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - Moncaut, Natalia AU - Moncaut N AD - Genetic Manipulation Service, The Francis Crick Institute, London, United States. FAU - Rosewell, Ian AU - Rosewell I AD - Genetic Manipulation Service, The Francis Crick Institute, London, United States. FAU - Nye, Emma AU - Nye E AD - Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom. FAU - Jones, Neil AU - Jones N AD - London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom. FAU - Heride, Claire AU - Heride C AUID- ORCID: 0000-0003-1927-9577 AD - London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom. FAU - Gersch, Malte AU - Gersch M AD - Max Planck Institute of Molecular Physiology, Dortmund, Germany. FAU - Wu, Min AU - Wu M AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - Dinsmore, Christopher J AU - Dinsmore CJ AD - FORMA Therapeutics, Watertown, United Kingdom. FAU - Hammonds, Tim R AU - Hammonds TR AD - London Bioscience Innovation Centre, CRUK Therapeutic Discovery Laboratories, London, United Kingdom. FAU - Kim, Sunkyu AU - Kim S AD - Incyte, Wilmington, United States. FAU - Komander, David AU - Komander D AD - Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Royal Parade, and Department of Medical Biology, University of Melbourne, Melbourne, Australia. FAU - Urbe, Sylvie AU - Urbe S AD - Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. FAU - Clague, Michael J AU - Clague MJ AUID- ORCID: 0000-0003-3355-9479 AD - Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. FAU - Kessler, Benedikt M AU - Kessler BM AUID- ORCID: 0000-0002-8160-2446 AD - Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Behrens, Axel AU - Behrens A AUID- ORCID: 0000-0002-1557-1143 AD - Adult stem cell laboratory, The Francis Crick Institute, London, United Kingdom. AD - Cancer Stem Cell Laboratory, Institute of Cancer Research, London, United Kingdom. AD - Imperial College, Division of Cancer, Department of Surgery and Cancer, London, United Kingdom. AD - Convergence Science Centre, Imperial College, London, United Kingdom. LA - eng GR - FC001039/ARC_/Arthritis Research UK/United Kingdom GR - FC001039/MRC_/Medical Research Council/United Kingdom GR - FC001039/WT_/Wellcome Trust/United Kingdom GR - 097813/Z/11/Z/WT_/Wellcome Trust/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - FC001039/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211012 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (DNA-Binding Proteins) RN - 0 (MYCBP protein, human) RN - 0 (Transcription Factors) RN - 0 (USP28 protein, mouse) RN - EC 3.4.19.12 (Ubiquitin Thiolesterase) SB - IM MH - Animals MH - DNA-Binding Proteins/*genetics/metabolism MH - Disease Models, Animal MH - *Gene Deletion MH - Humans MH - Lung Neoplasms/*genetics MH - Mice MH - Neoplasms, Squamous Cell/*genetics MH - Transcription Factors/*genetics/metabolism MH - Ubiquitin Thiolesterase/*genetics/metabolism PMC - PMC8553340 OTO - NOTNLM OT - USP28 OT - biochemistry OT - c-MYC OT - cancer biology OT - chemical biology OT - human OT - squamous cell lung cancer COIS- ER, AP, LL, TC, HS, AD, GV, ER, CD, NM, IR, EN, MG No competing interests declared, AT Andrew P Turnbull is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. APT declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. WK Wojciech W Krajewski is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. WWK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. DG Dave Guerin is affiliated with Constellation Pharmaceuticals (Boston, USA), for which no financial interests have been declared. DG declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. JK Jeffrey Kearns is affiliated with the Novartis Institutes for BioMedical Research (Boston, USA), for which no financial interests have been declared. JK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. SI Stephanos Ioannidis is affiliated with H3 Biomedicine (Cambridge, MA, USA), for which no financial interests have been declared. SI declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. MK Marie Katz is affiliated with Valo Health (Boston, USA), for which no financial interests have been declared. MK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. CM Crystal McKinnon is affiliated with Valo Health (Boston, USA), for which no financial interests have been declared. CM declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. JO Johnathan O'Connell is affiliated with Valo Health (Boston, USA), for which no financial interests have been declared. JOC declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. NJ Neil Jones is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. NJ declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. CH Claire Heride is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. CH declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. MW Min Wu is affiliated with Disc Medicine (Cambridge, MA, USA), for which no financial interests have been declared. MW declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. CD Christopher J Dinsmore is affiliated with Disc Medicine (Cambridge, MA, USA), for which no financial interests have been declared. CJD declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. TH Tim R Hammonds is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. TRH declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. SK Sunkyu Kim is affiliated with Incyte (Wilmington, DE, USA), for which no financial interests have been declared. SK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. DK DK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. SU SU declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. MC MJC declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. BK BMK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. AB AB declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. EDAT- 2021/10/13 06:00 MHDA- 2021/11/25 06:00 PMCR- 2021/10/12 CRDT- 2021/10/12 08:41 PHST- 2021/06/24 00:00 [received] PHST- 2021/10/10 00:00 [accepted] PHST- 2021/10/13 06:00 [pubmed] PHST- 2021/11/25 06:00 [medline] PHST- 2021/10/12 08:41 [entrez] PHST- 2021/10/12 00:00 [pmc-release] AID - 71596 [pii] AID - 10.7554/eLife.71596 [doi] PST - epublish SO - Elife. 2021 Oct 12;10:e71596. doi: 10.7554/eLife.71596.