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

Angelo Agathanggelou, Edward Smith, Nicholas J. Davies, Marwan Kwok, Anastasia Zlatanou, Ceri E. Oldreive, Jingwen Mao, David Da Costa, Sina Yadollahi, Tracey Perry, Pamela Kearns, Anna Skowronska, Elliot Yates, Helen Parry, Peter Hillmen, Celine Reverdy, Remi Delansorne, Shankara Paneesha, Guy Pratt, Paul Moss, A. Malcolm R. Taylor, Grant S. Stewart and Tatjana Stankovic

Key points

  • USP7 is overexpressed and regulates homologous recombination repair in CLL cells.

  • USP7 inhibition is selectively cytotoxic to CLL cells independently of ATM and p53, and synergizes with chemotherapy.

Abstract

The role of the deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whilst previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we have recently shown 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 independent of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitizes p53-defective, chemoresistant 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.

  • Submitted December 21, 2016.
  • Accepted April 29, 2017.