Biology Reference
In-Depth Information
stress. For this reason, interference with these latter two checkpoints has
become an interesting and promising strategy to sensitize G1-deficient cancer
cells to DNA damage therapy.
II. The Concept of Synthetic Lethality in Cancer Therapy
Advances in the understanding of the pathways affected by these cancer-
specific mutations are beginning to lead to novel therapeutic approaches aimed
at killing cancer cells based on the concept of synthetic lethality. Synthetic
lethal interactions are defined as two genetic alterations that, when occurring
together, cause cell death, while neither mutation alone is lethal (
Fig. 2
A). This
phenomenon was originally revealed through experiments in yeast and fruit
flies,
38,39
but variations on this basic concept have clear application to cancer
therapy.
40,41
Some of the changes in the molecular nature of cancer cell
signaling may serve as sensitizing mutations, leading to a dependency for
survival on certain molecules or pathway combinations that are not necessary
in normal cells, providing interesting therapeutic opportunities if these path-
way combinations can be selectively targeted and/or engaged.
Although synthetic lethality has been classically described for genetic alter-
ations, it can also be applied to other cellular perturbations such as the action of
small molecules or environmental factors such as DNA-damaging ionizing radi-
ation. Therefore, pharmacological inhibition of one gene product that is synthet-
ic lethal in combination with a preexisting cancer mutation will selectively target
and kill the tumor cell, while healthy cells not carrying the cancer-specific
mutation tolerate the treatment remaining largely unharmed. In addition, syn-
thetic lethality-based therapies provide the possibility to exploit treatments that
endogenously manipulate molecular targets that are not easily accessible for
inhibition by small molecules, in addition to exploiting loss-of-function mutations
in tumor suppressor genes to enhance the effects of DNA-damaging agents.
42
III. Synthetic Lethality Between PARP1 and BRCA1/2 as a Model
for Enhancing DNA Damage-Induced Cell Death
The potential for using synthetic lethality in the context of DNA damage
signaling as a principle for anticancer therapy has been demonstrated by recent
findings on the interaction between
PARP1
and
BRCA1/2
.
43,44
These genes are
template for HR-mediated repair. (D) HR-mediated repair of DSBs induced by PARP inhibition is
not available in BRCA1/2-deficient cancer cells. Instead, breaks are resolved by error-prone repair
pathways, such as NHEJ and SSA, leading to progressive genomic instability and ultimately cell
death as a consequence of mitotic catastrophe (modified from Ref.
37
).
