PARP-inhibitor-induced synthetic lethality for acute myeloid leukemia treatment

Abstract

Please cite this article as: Zhao L, Eric So CW, PARPi-induced synthetic lethality for acute myeloid leukaemia treatment, Experimental Hematology (2016), doi: 10.1016/j.exphem.2016.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Genomic instability is one of the most common and critical characteristics of cancer cells. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTThe combined effect of replication stress and DNA damage repair defects associated with various oncogenic events drives genomic instability and the disease progression. However, these DNA repair defects found in cancer cells can also provide unique therapeutic opportunities, which also form the basis of synthetic lethal targeting of solid tumours carrying BRCA mutations. While the idea of utilising synthetic lethality as a therapy strategy has been gaining momentum and progress in various solid tumours, its application in leukaemia still largely lags behind. In this article, we will review the recent advances in understanding the roles of DNA damage response in acute myeloid leukaemia (AML) and examine the potential therapeutic avenues of using PARP inhibitors in AML treatment.

The DNA damage response pathway in normal hematopoiesis and malignancies

“…The inhibition of PARP1 induces the formation of SSBs, which then evolve into DSBs that in normal cells are repaired by the HR [45]. However, in cells where the HR is defective, such as those with mutated BRCA1 or BRCA2, PARP1 inhibition induces an excessive accumulation of genotoxic damage which triggers cell death, and this synthetic lethality effect has been effectively exploited in the treatment of Brca1-defective solid tumors [46]. More recent studies have shown that PARP1 inhibitors may also find application for the treatment of certain hematological malignancies.…”

The Potential of Targeting DNA Repair Deficiency in Acute Myeloid Leukemia

“…While one defect is not generally detrimental to a cells survival, the synthetic introduction of another pathway defect can be enough to push a cell into such disarray that the only option it faces is apoptosis [23].…”

DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

“…Acute myeloid leukaemia (AML) is a malignant disorder characterised by the accumulation of genetic aberrations in the myeloid haematopoiesis linage, that can be risk classified according to specific gene mutations (1). Understanding the AML genome promises new therapeutic strategies that involve synthetic lethal interactions (2). Thus, in this study we compare the effects of combining olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in malignancies bearing homologous recombination deficiencies (2) and daunorubicin (ODC) with the standard daunorubicin-cytarabine (CDR) that models the "7+3" induction regimens.…”

“…Understanding the AML genome promises new therapeutic strategies that involve synthetic lethal interactions (2). Thus, in this study we compare the effects of combining olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in malignancies bearing homologous recombination deficiencies (2) and daunorubicin (ODC) with the standard daunorubicin-cytarabine (CDR) that models the "7+3" induction regimens. Two AML cell lines were chosen: OCI/AML3 and THP-1.…”

“…OCI/AML3 is characterised by a common and impactful co-occurrence of mutations in both nucleophosmin gene (NPM1), involved in DNA single strand break repairs and DNA methyltransferase 3 alpha gene (DNMT3A), involved in resistance to anthracycline-induced DNA damage (3)(4)(5). THP-1 is characterised by mutations and deletions in PTEN, MLL-AF9, MLLT3, TP73, CDKN2A/B (6), which makes it susceptible to the effects of olaparib, particularly through the presence of a partial deletion in PTEN gene (2).…”