Biology Reference
In-Depth Information
inhibitors of each pathway
e
either as single agents or in
rational combinations
e
are discussed in the following
chapters.
Our ever-expanding knowledge of DNA repair and
DNA damage response is paramount to the ongoing
translational research that seeks to create new ways of
fighting diseases. Much is yet to be learned about the
regulation of DNA damage response and repair
processes. The concept of relatively straight, strictly
hierarchical DNA repair pathways that operate in
a cascade sequence is being replaced with a model of
robust networks of pathway crosstalk and interactions
(
Table 1.6
). As researchers uncover more of those inter-
actions, it paints a picture of how complex normal
DNA repair processes function, how rescue signaling
is provided from a number of proteins
e
and how carci-
nogenesis can modify signaling networks to compensate
for mutagenic losses.
30
Investigators are still in the early stages of discov-
ering how the intricacies of DNA repair translate to
acquired or intrinsic resistance in cancers, but the
fact that cancers have astonishing abilities to adapt
and transform as compensatory mechanisms is well
established. Cancer is a collection of genetic errors;
and, as more errors collect, their cumulative pattern of
expression or mutation blurs. The ever-morphing nature
of most cancers contributes to the fact that they do not
possess one unique determinant for resistance. Instead,
heterogeneous resistance to therapeutics arises from
sequential “reprogramming” of various aspects of
tumor functionality, which involves contributions from
multiple proteins and multiple signaling pathways.
30
Even less is known about tumor microenvironments,
epigenetic maintenance and stability, and how changes
in both influence cancers.
5
All
these factors affect
tumor survival, and most of
them are yet
to be
characterized.
Scientists' limited understanding of DNA repair
processes in normal cells and tumor cells, as well as
the extent of heterogeneity involved in tumorigenic
transformation, has contributed to the relatively modest
success that has been achieved in treating many cancers.
Investigators have made great strides in making anti-
cancer treatments more selective in targeting only tumor
activity (
Figure 1.7
), but collateral damage is still a reality
of all such therapeutics. However, the concept of
synthetic lethality is a powerful guidepost for research
development in truly targeted
e
even customized
e
treatments for cancer. Synthetic lethality can be applied
in many ways to development of inhibitors: in loss of
particular cell-cycle checkpoints, acute silencing of
a perpetually proliferative signal, genetic streamlining,
and novel drug-gene and drug-drug interactions.
3
Knowledge of DNA repair is highly relevant to every
aspect of oncology. The more that we understand of the
molecular mechanisms behind DNA damage tolerance,
damage response, and repair, the more fruitful our
efforts can be in creating more effective clinical thera-
peutics and determining how to best use and combine
DNA repair inhibitors with other treatments for the
greatest clinical gains. This is not a wish; it is a compul-
sion. The numbers behind cancer speak volumes.
TABLE 1.6 Summary of Overlap and Crosstalk between Major
DNA Repair Pathways
Overlap
Mechanism
In DR, if O
6
-methylguanine-DNA methyltransferase
(MGMT) is unsuccessful in removing O
6
-
methylguanine, the MMR pathway can recognize and
fix O
6
-methylguanine mispairs
26
DR/MMR
Larger adducts at the O
6
-position of guanine that
MGMT cannot repair are repaired by NER
13,26
DR/NER
DR/BER
Mismatch pairs and other alkylation adducts that DR
does not repair are repaired by BER
26,28
DR/MMR
MMR can repair guanine/thymine mismatches that are
left behind when MGMT repairs guanine post-
replicatively. Futile MMR cycles create DSBs, which
either induces apoptosis or repair by HR or NHEJ
13
W
HY WE MUST BEAT CANC
ER
BER/NER
BER is primarily responsible for repairing oxidative
DNA damage, but NER can serve as a backup for
repairing some minor damage
26
Since 1987, the cost of cancer has more than doubled
every 15 years. The American Cancer Society estimated
that 56,490 people died from cancer in 2010,
31
and the
total direct medical cost to treat cancer that year was
$102.8 billion
e
a 9% jump from just one year prior.
32
Total costs, including loss of productivity due to
morbidity and mortality, are 150% more than the cost
of treatments.
31
Although cancer patients are living
longer
e
either cured or in extended remission
e
the
burden of care keeps rising, taking a tremendous toll
on society. In the quest for better treatment, one of
the great hopes
BER/HR
If BER does not repair single-strand DNA breaks
(SSBs), they may lead to double-strand breaks (DSBs),
which HR can repair
26
BER/HR/
NHEJ
If BER fails to repair SSBs, they can be repaired at
replication by HR; if signaling arrests cell cycle at G1,
then NHEJ can repair the breaks
15
HR/NHEJ
HR can repair DNA DSBs that the NHEJ pathway fails
to process
13
Abbreviations: BER
¼
base excision repair; DR
¼
direct repair; HR
¼
homologous
recombination; NER
¼
nucleotide excision repair; NHEJ
¼
non-homologous end
lies
in developing DNA repair
joining.
