PARP1 expression, activity andex vivosensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia

Abstract

In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors.We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 – 190052 pmol PAR/106 cells) compared to that seen in healthy volunteer lymphocytes (2451 – 7519 pmol PAR/106 cells). PARP activity was associated with PARP1 protein expression and endogenous PAR levels. PARP activity was not associated with p53 or ATM loss, Binet stage, IGHV mutational status or survival, but correlated with Bcl-2 and Rel A (an NF-kB subunit). Levels of 8-hydroxy-2′-deoxyguanosine in DNA (a marker of oxidative damage) were not associated with PAR levels or PARP activity. The potent PARP inhibitor, talazoparib (BMN 673), inhibited CD40L-stimulated proliferation of CLL cells at nM concentrations, independently of Binet stage or p53/ATM function.PARP activity is highly variable in CLL and correlates with stress-induced proteins. Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib.

Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP

“…PARPi cause DNA damage accumulation and G2/M cell cycle arrest (23,24). Effects of ABT-263 and BMN 673 on DNA double-strand break induction and cell cycle progression were thus examined to dissect the potential mechanisms of cell growth inhibition induced by the combination treatment.…”

Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia

“…Moreover, olaparib displayed activity in ATM-defective lymphoblastoid cell lines, the ATM -mutant mantle cell lymphoma cell line Granta-519, and ATM -defective primary CLL cells 54 , 55 . However, the ATM status-dependent specificity of PARP inhibitor sensitivity recently came into question, when it was shown that the PARP1/2 inhibitor talazoparib (BMN-673) displayed activity against CLL cells ex vivo independent of ATM and HR status 56 . Here we developed an autochthonous, non-transplant mouse model of ATM -deficient CLL to unequivocally demonstrate the in vivo activity and specificity of olaparib against ATM -defective CLL.…”

The DNA damage response pathway in normal hematopoiesis and malignancies

“…It should be noted, however, that a recent study, while confirming the cytotoxic activity of the potent PARP inhibitor talazoparib in patient-derived CLL cells, failed to find an association between PARP activity, ATM loss, or levels of oxidative DNA damage [53].…”