Biology Reference
In-Depth Information
CHAPTER
14
Future Directions with DNA Repair Inhibitors:
A Roadmap for Disruptive Approaches
t o Cancer Therap y
Mark R. Kelley
Indiana University School of Medicine, Indianapolis, IN
Many intrinsic and extrinsic factors threaten genome
stability; and, when it is disrupted, a path of uncon-
trolled growth and cancer begins. The previous chapters
of this topic described in detail the workings of DNA
damage response and repair pathways, pathway alter-
ations in cancers, potential biomarkers for pathways,
and possible clinical applications of inhibitors for partic-
ular pathway proteins. Learning the intricacies of effi-
cient, accurate DNA damage response and repair will
enable researchers to create new anticancer agents that
capitalize on cancer-specific alterations to those repair
mechanisms, which are often early events in tumori-
genic transformation. 1 e 6 The more effectively we can
inhibit the processes by which cancer cells replicate,
proliferate, and spread, the more inroads we will make
in the fight against cancer.
Early events in carcinogenesis include (1) activation
of oncogenes, (2) silencing of tumor-suppressor genes,
and (3) alterations to other genes involved in cell
survival and growth. Excessive growth signals foster
unchecked growth, but that comes with a price: endog-
enously generated DNA lesions. 2,5 Disruptions in DNA
repair pathways predispose cells to accumulating
damage, and subsequently, mutations. 2 However,
both mutations and heterozygous polymorphisms can
alter DNA damage response and repair processes. 7
Abundant evidence exists that, as cancers progress,
they become increasingly more malignant by accumu-
lating more mutations in their DNA repair proteins,
which may limit or extinguish the functionality of
a repair pathway or other key element of DNA
maintenance. 5
One would think that possessing a reduced reper-
toire of DNA repair processes would naturally make
cancer cells more susceptible to cytotoxic treatments,
but the opposite has borne itself out repeatedly
e
more than likely due to the resultant genomic insta-
bility caused by tumor cells' altered DNA repair
capabilities. Although mutagenic cells progressively
lose some of their ability to repair DNA damage,
they have stunning compensatory abilities that we
are just beginning to understand; and those abilities
can greatly reduce the cytotoxic effects of chemo-
therapy and radiotherapy. 2,5,7 In addition, mutations
to DNA checkpoint proteins can allow DNA damage
to go unchecked as cancer cells replicate, contributing
to damage tolerance, uncontrolled proliferation, and
an increasingly heterogeneous tumor that
is more
difficult to treat. 8
Because of this, molecular characterization of DNA
repair pathways is a critical prerequisite for learning
how those pathways are altered in cancer cells. That
knowledge is key in uncovering new opportunities
for
creating effective
anticancer
treatments
that
can target
and circumvent
cancer's
resistance
mechanisms. 2,5
TOOLS IN THE TREATMENT AR SENAL
Today many inhibitors in development block the
activity of a key protein in an aspect of DNA damage
response or DNA repair. Using such inhibitors can
potentially increase the efficacy of existing chemo-
therapy 9,10 and radiotherapy regimens. 1 Thus, the very
alteration that gives rise to tumor transformation can
also help investigators create tumor-targeted treatments
that minimize damage to normal tissues. 1
 
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