Biology Reference
In-Depth Information
critical components of two different DNA damage repair pathways. PARP1 is
best appreciated for its role in facilitating base excision repair (BER), a mech-
anism used to fix chemically induced base mutations. This involves the tempo-
rary creation of single-strand DNA breaks and the possible exposure of modest
lengths of single-stranded DNA
45
(
Fig. 2
B). Exactly how PARP1 participates in
BER at the molecular level remains unclear, but known substrates of PARP1
include histones and PARP1 itself. BRCA1 and 2 are major components of the
error-free homologous recombination (HR) repair for DNA DSBs. Deficiency
in BRCA genes leads to high susceptibility for breast and ovarian cancer, as
cells become dependent on the repair of DSBs by alternative mechanisms,
including nonhomologous end-joining (NHEJ) or single-strand annealing
(SSA). These repair mechanisms are error-prone, which ultimately results
in increased genomic instability.
46
Studies by Bryant et al. and Farmer et al.
demonstrated that the inhibition of PARP1-dependent repair mechanisms
ultimately leads to the formation of DNA lesions that are dependent on HR
for resolution.
43,44
In normal cells with intact HR mechanisms, this results in
only minor survival differences after PARP inhibition (
Fig. 2
C). In BRCA1-
or 2-deficient cells, however, there is a dramatic increase of cell death in
response to PARP1 inhibitors caused by the absence of HR activity, most
likely resulting in genomic instability that cannot be rescued by alternative
repair mechanisms (
Fig. 2
D). PARP1 function is observed in response to a
wide variety of DNA lesions, and the extent to which the synthetic lethal
interaction between PARP1 and BRCA1/2 is dependent on BER is not
completely clear.
Nonetheless, these findings indicate that the inhibition of PARP1 can and
should be used as a therapeutic strategy to target
BRCA1
-or
2
-deficient
cancers. For this reason, PARP inhibitors are currently being evaluated in
clinical trials; an initial phase I clinical trial using the PARP1 inhibitor Olaparib
showed antitumor activity in cancer associated with the
BRCA1
or
2
mutation
and reported a few adverse effects in patients.
47
Additional studies with Ola-
parib confirmed efficacy and tolerability in patients
48
as well as antitumor
activity in
BRCA1/2
mutation ovarian cancer, which was associated with in-
creased sensitivity to platinum-based chemotherapy.
49
PARP1 inhibition in a
phase II trial has now been shown to result in a favorable therapeutic index for
BRCA-deficient breast cancer patients.
50
In addition to Olaparib, a variety of
other PARP inhibitors such as Inaparib (BSI-201), AG014699, ABT-888, CEP-
9722, and INO-1001 have been developed and are currently being tested in
different studies.
51-53
The best clinical results seem to be emerging from the
inhibitors that have the lowest IC
50
values, indicative of strong PARP binding
(A. Ashworth, personal communication). At present, there are more than 50
clinical trials ongoing worldwide for different tumor types, many in combina-
tion with DNA-damaging chemotherapy.
54
