Biology Reference
In-Depth Information
The results from these trials have to be interpreted carefully, particularly with
respect to long-term follow-up. PARP1-deficient mice show a predisposition to
epidermal hyperplasia
55
and mammary carcinomas,
56
indicating that long-term
treatment with PARP inhibitors might cause severe adverse effects. In addition,
studies on BRCA2-deficient cancer cells treated in culture indicate that secondary
mutations in the BRCA2 gene restore HR function and, as a consequence,
resistance to PARP inhibitors.
57,58
A deeper understanding of the specific role of
PARP in cancer cells and the consideration of factors such as the levels of PARP-1
expression in tumors, and the optimal dosing schedule for PARP inhibitors/che-
motherapy combinations may improve the selection of patients for PARP inhibitory
therapy. Nevertheless, the success of the BRCA/PARP studies has established a
paradigm for synthetic lethality as a functionally new concept in anticancer therapy.
IV. Synthetic Lethality in the Context of p53 Mutations
Synthetic lethal interactions not only occur between two genetic mutations
or by single-gene mutations in combination with inhibition of other gene
products by small molecules, but also become apparent when cells are exposed
to environmental factors such as extrinsic cellular stress by DNA-damaging
ionizing radiation or cytotoxic chemotherapy. The loss of one tumor suppressor
gene alone may not change the survival of cancer cells in response to genotoxic
stress as compared to normal cells. Inhibition of a second pathway that engages
a synthetic lethal interaction with the lost tumor suppressor, however, might
result in a dramatic difference in the chemosensitivity and enhanced
chemotherapy/radiation-induced cell death in tumors following DNA damage,
but not necessarily under unstressed conditions prior to the damage.
As mentioned earlier, the DNA damage response and DNA repair pathways
are among the most commonly perturbed networks in human cancers.
12-20
Several recent studies have therefore identified specific components of the
DNA damage response pathway as promising candidates for targeting synthetic
lethal interactions with commonly lost tumor suppressor genes such as
p53
in
the context of genotoxic therapy. The focus of many of these studies has been on
the kinases regulating the intra-S and G2/M checkpoints, as kinases are well
established as druggable targets.
A. Synthetic Lethality Between p53 and the ATR/Chk1
Signaling Pathway
The ATR/Chk1 signaling pathway is activated mainly by DNA single-strand
breaks (DSSs) and stalled replication forks. These kinases function in the
regulation of cell cycle arrest following genotoxic stress, but are also critical
