Biology Reference
In-Depth Information
FIGURE 1.1
Cancer progression. Cumula-
tive mutagenesis, genetic streamlining, and
a progressively heterogeneous phenotype are
hallmarks of cancer progression.
Image courtesy
of Shutterstock Images.
a cancer, then discovering the second entity that can
create a synthetic lethal interaction should be both
highly effective and highly selective in causing cancer
cell death, because cells that contain a normal copy of
either gene should not be affected.
3,8
The idea of synthetic lethality is not new; Dobzhan-
sky first described it in 1946. However, it took another
half century before anyone suggested that the concept
could be applied to cancer therapeutics, when Hartwell
et al.
posited this in 1997.
8
Thus, targeting a weakness of
cancer, such as abnormal expression (deficiency, overac-
tivity) or some other feature that promotes cancer
growth,
3,5
could provide a solution to the conundrum
of killing cancer cells while sparing normal cells.
The most likely opportunities to induce synthetic
lethality are related to DNA damage response and
repair. Although much remains to be learned
regarding the sequential biochemical changes that
transform normal cells into cancer cells, we do know
that many cancer cells are defective in their ability to
recognize and respond to DNA damage. Such defects
can lead to point mutations, copy number changes,
structural abnormalities such as translocations, and
other mutagenic transformations. If those defects can
be exploited
e
especially early in the process of carci-
nogenesis
e
then it would keep cancerous cells from
acquiring a more virulent mutational phenotype
(
Figure 1.2
). Furthermore, developing the right inhibi-
tors to capitalize on such defects would create a lethal
liability in cancer cells. Moreover, such agents should
have higher therapeutic indices than current anti-
cancer drugs because relatively low doses of inhibitors
should affect cancer cells without causing collateral
damage.
3
Real-world scenarios are more complicated than
conceptualizations, and many questions
regarding
FIGURE 1.2
Genetic streamlining and how synthetic lethality capitalizes on it. The width of the dark gray bars indicates the relative amount
of cellular proliferation in normal cells versus cancer cells. The light gray bars indicate how cancers can lose some of their DNA repair abilities
over time as more mutations accumulate. A synthetic lethal reaction capitalizes on a cancer's weakness in one area to create DNA damage that
the cancer no longer is able to repair.
Original artwork created by Lana Christian, CreateWrite, Inc.
