Abstract
Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.
Highlights
Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials
Basic research into DNA damage repair biochemistry led to the identification of PARP, the inhibition of which, almost 40 years later, is showing great promise in the treatment of BRCA-deficient ovarian, breast, prostate and pancreatic cancer patients [87,88,89]
Basic research into DNA damage repair biochemistry led to the identification of and others discussed here has shown that PARP inhibitors may have potential in treating patients
Summary
Genome instability, characterized by the accumulation of mutations and chromosomal alterations in the genome, is both a hallmark and a driver of cancer [1,2]. It was originally proposed that PARP inhibition blocked base excision repair and single strand break repair pathways increasing reliance on BRCA-dependent repair This model has been challenged [12] and more recent studies have shown that olaparib reduces cell proliferation by inducing replication stress [13] and that olaparib sensitivity is due to engagement of homologous recombination repair (HRR) at replication forks [14]. HRR is active in S phase at stalled replication forks and in G2 phase of the cell cycle after DSBs have been resected to contain long ssDNA overhangs on their 3’ ends [28] These long regions of ssDNA are bound by replication protein A (RPA) and BRCA2 plays a role in the replacement of RPA with RAD51, the protein that initiates strand invasion and the search for a homologous DNA sequence during HRR [28]. Cell lines derived from A–T patients and ATM knock out mice are hypersensitive to IR and other chemotherapeutic agents [43,44], raising the possibility that cancers with loss of ATM may be more sensitive to DNA damaging agents than their ATM-proficient counterparts [45]
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