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Page 674 Murthy et al. Cancer Drug Resist 2019;2:665-79 I http://dx.doi.org/10.20517/cdr.2019.002

Analogously to 53BP1, the protein encoding by the gene REV7 also antagonizes HR, and in vitro studies in
[64]
mouse and human cell lines have shown that loss of REV7 restores HR and leads to PARPi resistance .

Targeting upstream mediators of the DNA damage response, such as ATM and ATR, in combination with
PARP inhibition, could be a strategy to circumvent the development of PARPi resistance from 53BP1 or
REV7 loss.

2. Replication fork dynamics: Besides their role in DNA repair, PARP and the BRCA proteins are
also involved in DNA replication and the stabilization of replication forks. A preclinical study
showed that protection and stabilization of replication forks rescues BRCA-deficient stem cells,
[65]
independent of any effect on HR . This same study found that a mechanism of replication fork protection
is the inhibition of nuclease recruitment to stalled replication forks, which protected the nascent DNA
strands from degradation. The resulting replication fork stabilization conferred resistance to PARPis and
[66]
platinum chemotherapy . Interestingly, Hill et al. evaluated patient-derived ovarian cancer organoids,
[65]
and found that a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity,
whereas a functional defect in replication fork protection correlated more strongly with carboplatin
sensitivity. Since some patients with platinum-resistant ovarian cancer do respond to subsequent PARP
inhibition (and vice versa), PARP inhibitor and platinum resistance mechanisms do not completely overlap.
Differing effects of these two drug classes on DNA repair and replication fork dynamics may underlie the
differences in responses.

The complex relationship between numerous factors and pathways in replication fork stabilization,
including modulators of the cell cycle, is an active area of research, and therapeutic strategies addressing
this mechanism of PARPi resistance are emerging (topoisomerase inhibition, cell cycle control).

3. PARylation effects: PARP’s function in DNA repair depends on its ability to catalyze PARylation of
nuclear proteins. Poly-ADP-ribose glycohydrolase (PARG) is an antagonizing enzyme that digests poly-
ADP-ribose moieties into ADP-ribose, and effectively “undoes” PARylation. Endogenous PARG seems to
be crucial for the success of PARP inhibitor treatment, based on preclinical studies that have shown that
[67]
PARG depletion partially rescues PARP1 signaling in the setting of PARP inhibitor treatment . The same
authors were also able to show that a subset of human serous ovarian and triple negative breast tumors not
yet treated with PARP inhibition have PARG-negative clones, suggesting that PARG-negativity could be
a biomarker predicting lack of response to PARP inhibition. Further clinical validation of this concept is
needed.

4. Loss of PARP1: Immunohistochemistry studies have shown widely variable PARP1 levels in patients
with ovarian and breast cancer, irrespective of BRCA status, but association with outcomes has been
mixed [68,69] . Because the clinical PARPis vary in their PARP targets, chemical structures, and PARP
trapping capabilities, treatment with a secondary PARPi could potentially be efficacious in a resistant
tumor, but further study is needed .
[70]

5. Drug efflux: Resistance to any drug can develop from up-regulation of drug efflux pumps
(p-glycoproteins). In the case of PARPis, mouse models of BRCA1-deficient breast tumors treated with
olaparib showed up-regulation of p-glycoproteins with ongoing treatment and maintenance. Furthermore,
treatment with a p-glycoprotein inhibitor (tariquidar) following relapse on olaparib re-sensitized the
tumor to olaparib and led to tumor regression . Because p-glycoprotein inhibitors lack specificity and
[13]
are associated with significant toxicity, targeting upstream regulators of these drug efflux pumps may be a
better tolerated strategy, and is being evaluated .
[70]