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

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