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  3. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

  • Sci Rep. 2020 Mar 24;10(1):5324. doi: 10.1038/s41598-020-62076-x.
Nathan J Schauer  # 1 2,  Xiaoxi Liu  # 1 2,  Robert S Magin 1 2,  Laura M Doherty 1 2 3,  Wai Cheung Chan 1 2,  Scott B Ficarro 1 4 5,  Wanyi Hu 1,  Rebekka M Roberts 1,  Roxana E Iacob 6,  Björn Stolte 7 8 9,  Andrew O Giacomelli 9 10 11,  Sumner Perera 12,  Kyle McKay 13,  Sarah A Boswell 3,  Ellen L Weisberg 10,  Arghya Ray 10 14,  Dharminder Chauhan 10 14,  Sirano Dhe-Paganon 1 2,  Ken C Anderson 10 14,  James D Griffin 10,  Jianing Li 13,  William C Hahn 9 10 11,  Peter K Sorger 3,  John R Engen 6,  Kimberly Stegmaier 7 9,  Jarrod A Marto 1 4 5,  Sara J Buhrlage 15 16
Affiliations

Affiliations

  • 1 Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Systems Biology and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Oncologic Pathology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 6 Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
  • 7 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
  • 8 Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany.
  • 9 The Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 11 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 12 Harvard College, Cambridge, MA, USA.
  • 13 Department of Chemistry, University of Vermont, Burlington, VT, USA.
  • 14 The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 15 Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA. saraj_buhrlage@dfci.harvard.edu.
  • 16 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. saraj_buhrlage@dfci.harvard.edu.
  • # Contributed equally.
PMID: 32210275 DOI: 10.1038/s41598-020-62076-x
Abstract

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating Enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in Cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multi-substrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structure-guided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses Cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of ~500 Cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A.

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