USP7 inhibition alters homologous recombination repair and targets CLL cells independently of ATM/p53 functional status

Blood. 2017 Jul 13;130(2):156-166. doi: 10.1182/blood-2016-12-758219. Epub 2017 May 11.

Abstract

The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome. We demonstrate that USP7 is upregulated in CLL cells, and its loss or inhibition disrupts homologous recombination repair (HRR). Consequently, USP7 inhibition induces significant tumor-cell killing independently of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitized p53-defective, chemotherapy-resistant CLL cells to clinically achievable doses of HRR-inducing chemotherapeutic agents in vitro and in vivo in a murine xenograft model. Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Line, Tumor
  • DNA Damage
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Mice
  • Mice, Inbred NOD
  • Primary Cell Culture
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinational DNA Repair / drug effects*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitin-Specific Proteases / antagonists & inhibitors
  • Ubiquitin-Specific Proteases / genetics*
  • Ubiquitin-Specific Proteases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Pyrazoles
  • Pyrimidines
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • ibrutinib
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitin-Specific Proteases
  • Usp7 protein, mouse