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The scope and space limitations of this review have unfortunately
meant that I have not been able to separately cite many of the
original publications that have contributed substantially to the
literature. I sincerely apologize to the authors of these publications.
I thank S.-J. Dawson for critical appraisal of the manuscript and
all of the members of the Dawson laboratory for helpful
discussions. M.A.D. is the senior fellow for Leukaemia Foundation
Australia. The National Health and Medical Research Council
of Australia, Cancer Council Victoria, and the Snowdome
Foundation support research in the Dawson laboratory. M.A.D.
is on the scientific advisory board of Cancer Therapeutics CRC
(CTx), a company developing new cancer drugs, and is a paid
consultant for Celgene and Pfizer.
PARP inhibitors: Synthetic lethality
in the clinic
Christopher J. Lord1 and Alan Ashworth2*
PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the
first clinically approved drugs designed to exploit synthetic lethality, a genetic concept
proposed nearly a century ago. Tumors arising in patients who carry germline mutations
in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of
DNA repair defect. PARPi also show promising activity in more common cancers that
share this repair defect. However, as with other targeted therapies, resistance to PARPi
arises in advanced disease. In addition, determining the optimal use of PARPi within drug
combination approaches has been challenging. Nevertheless, the preclinical discovery
of PARPi synthetic lethality and the route to clinical approval provide interesting lessons
for the development of other therapies. Here, we discuss current knowledge of PARP
inhibitors and potential ways to maximize their clinical effectiveness.
DNA damage and its repair or lack thereof are central to the induction of mutations, which drive the development of nearly all cancers. Healthy cells defend themselves against the deleterious effects of DNA damage through an interrelated series of molecular
pathways, the DNA damage response (DDR), that
recognize DNA damage, stall the cell cycle, and
mediate DNA repair, thus maintaining the integrity of the genome. Key to the DDR are the
poly(ADP-ribose) polymerase 1 and 2 (PARP1 and
PARP2) enzymes, DNA damage sensors and signal
transducers that operate by synthesizing negatively
charged, branched poly(ADP-ribose) (PAR) chains
(PARylation) on target proteins as a form of posttranslational modification (1). PARP1 binds damaged DNA at single-strand DNA breaks (SSBs)
and other DNA lesions, an event that causes a
series of allosteric changes in the structure of
PARP1 that activate its catalytic function (1–5)
(Fig. 1). This leads to the PARylation and recruitment of DNA repair effectors such as XRCC1, as
well as the remodeling of chromatin structure
around damaged DNA as part of the DNA repair process. PARP1 eventually PARylates itself
(autoPARylation). The negative charge that PAR
chains impart upon PARP1 likely causes its release
from repaired DNA (1–5) (Fig. 1B).
An understanding of the functions of PARP1
and PARP2 in the DDR drove long-standing ef-
forts to develop small-molecule PARP1/2 inhib-
itors (PARPi) (Fig. 1C) (6). The original rationale
was that PARPi could sensitize tumor cells to
conventional treatments that cause DNA damage,
including multiple chemotherapy or radiotherapy
approaches, which remain the backbone of treat-
ment for most cancer patients. By inhibiting PARP-
mediated repair of DNA lesions created by chemo-
or radiotherapy, greater potency might be achieved.
About 30 years ago, small-molecule nicotinamide
analogs were shown to inhibit PARylation and
to enhance the cytotoxicity of dimethyl sulfate,
a DNA damaging agent (7–9). Subsequent drug
discovery efforts led to the development of clin-
ical PARPi, including veliparib (Abbvie), rucaparib
(Pfizer/Clovis), olaparib (KuDOS/AstraZeneca), and
niraparib (Merck/Tesaro). More recently, a sec-
ond generation, more potent PARPi, talazoparib
(Lead/Biomarin/Medivation/Pfizer) has also been
developed (10). These PARPi all interact with the
binding site of the PARP enzyme cofactor, b nicotin-
amide adenine dinucleotide (b-NAD+), in the cata-
lytic domain of PARP1 and PARP2 but, as discussed
later, have differing effects in terms of their cytotoxic
potency and ability to “trap” PARP1 on DNA.
Carriers of deleterious heterozygous germ-line mutations in the BRCA1 and BRCA2 genes
have substantially elevated risks of developing
breast, ovarian, and other cancers (11–13). Because
the wild-type BRCA allele is lost during tumor-igenesis, these genes are considered classical
tumor suppressors. Both BRCA1 and BRCA2 proteins are critical to the repair of double-strand
DNA breaks (DSBs) by a process called homologous recombination repair (HRR), a form of DNA
repair that uses a homologous DNA sequence to
guide repair at the DSB. HRR is generally a “
conservative” mechanism, in that it restores the
original DNA sequence at the site of DNA damage
(14). When cells become HRR deficient, whether
driven by defects in BRCA1, BRCA2, or other
pathway components, nonconservative forms of
DNA repair predominate, such as nonhomologous end joining (NHEJ). These processes either
fuse broken DNA ends at the DSBs without using
a homologous DNA sequence to guide repair or
fuse regions of DNA close to the site of the DSB
that exhibit short regions of DNA sequence homology, deleting the intervening DNA sequence. The
preferential use of these nonconservative repair
mechanisms in the absence of HRR therefore
1The Cancer Research UK Gene Function Laboratory and
Breast Cancer Now Toby Robins Research Centre, The
Institute of Cancer Research, London SW3 6JB, UK.
2University of California, San Francisco (UCSF), Helen Diller
Family Comprehensive Cancer Center, 1450 Third Street, San
Francisco, CA 94158, USA.
*Corresponding author. Email: firstname.lastname@example.org (C.J.L.);
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