Antileukemic Efficacy in Vitro of Talazoparib and APE1 Inhibitor III Combined with Decitabine in Myeloid Malignancies

Abstract

Malignant hematopoietic cells of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) may be vulnerable to inhibition of poly(ADP ribose) polymerase 1/2 (PARP1/2) and apurinic/apyrimidinic endonuclease 1 (APE1). PARP1/2 and APE1 are critical enzymes involved in single-strand break repair and base excision repair, respectively. Here, we investigated the cytotoxic efficacy of talazoparib and APE1 inhibitor III, inhibitors of PARP1/2 and APE1, in primary CD34+ MDS/CMML cell samples (n = 8; 4 MDS and 4 CMML) and in primary CD34+ or CD34− AML cell samples (n = 18) in comparison to healthy CD34+ donor cell samples (n = 8). Strikingly, talazoparib and APE1 inhibitor III demonstrated critical antileukemic efficacy in selected MDS/CMML and AML cell samples. Low doses of talazoparib and APE1 inhibitor III further increased the cytotoxic efficacy of decitabine in MDS/CMML and AML cells. Moreover, low doses of APE1 inhibitor III increased the cytotoxic efficacy of talazoparib in MDS/CMML and AML cells. In summary, talazoparib and APE1 inhibitor III demonstrated substantial antileukemic efficacy as single agents, in combination with decitabine, and combined with each other. Hence, our findings support further investigation of these agents in sophisticated clinical trials.

DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets

“…APEX1 inhibitor has demonstrated a promising toxicity on primary AML cells in vitro, alone or in association with hypomethylating agent decitabine or PARP (poly(ADP-Ribose) polymerase) inhibitor talazoparib. Even if APEX1 expression levels did not significantly differ between responding and non-responding AML cells, APEX1 inhibitor appeared promising in normal karyotype AML (83% of the APEX1 inhibitor "responders") [59]. Our data support the potential therapeutic interest of DNA damage signaling and DNA repair inhibitors in CN-AML.…”

DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets

“…In preclinical studies, APEX1 inhibitor has demonstrated promising toxicity on primary AML cells in vitro, alone or in association with hypomethylating agent decitabine or with PARP inhibitor talazoparib. Even if APEX1 expression levels did not significantly differ between responding and non-responding AML cells, APEX1 inhibitor appeared promising in normal karyotype AML (83% of the patients with response to APEX1 inhibitor) [ 65 ]. Moreover, several other compounds targeting proteins involved in DNA repair mechanisms have already shown promising results as potential new anti-cancer drugs in pre-clinical studies, such as BLM [ 66 ], WRN [ 67 ], RAD52 [ 68 ], or MRE11 [ 69 ] inhibitors.…”

Role of Polymorphisms of NKG2D Receptor and Its Ligands in Acute Myeloid Leukemia and Human Stem Cell Transplantation

“…This mechanism seems to be specific for leukemia stem cells and enables them to escape immune surveillance and later to cause relapse of disease (69). This opens the possibility to use PARP inhibitors for AML patient (70), an approach that the first clinical trials are currently assessing (71)(72)(73).…”