Biology Reference
In-Depth Information
CHAPTER
10
Checkpoint Kinase and Wee1 Inhibitors
as A
nticancer Therape
utics
Susan Ashwell
AstraZeneca R&D Boston, Waltham, MA
G
ENERAL INTRODUCTION
additional networks of monitoring leading to the activa-
tion of cell cycle checkpoints or apoptosis.
DDR networks are fundamental in bacteria and lower
eukaryotes, as well as higher organisms, although in
higher eukaryotes there are additional defense systems
for the suppression of mutagenesis and tumorigenesis.
Cell cycle checkpoints, regulated by a sophisticated
network of sensors, transducers and mediators, are
induced following the detection of DNA damage, and
allow a pause in the cell cycle to provide time for repair
before continuing replication and entry into mitosis.
9,10
In addition, the expression of many DDR genes is
increased following DNA damage, in turn increasing
DNA damage surveillance, repair and apoptosis.
During the course of evolution, the process of apoptosis
that had evolved as part of the machinery necessary for
the elimination of altered cells or cells that are not longer
needed during development and normal tissue homeo-
stasis became incorporated into the DDR to eliminate
cells that could not complete the DNA repair
process.
11,12
Cellular fate by promoting either survival
or death is determined by factors such as the degree of
damage, capacity for repair, and is strongly dependent
on cell type.
13,14
While only part of the cellular machinery that recog-
nizes and responds to DNA damage, the signaling
cascade that specifically regulates cell cycle arrest
following DNA damage can itself be thought of as
a complex network of interconnected pathways consist-
ing of three main components
The human body contains approximately 10
13
cells
and each of them has been calculated to receive tens of
thousands of DNA lesions per day. Totaling these events
per individual, gives a number larger than there are
grains of sand on all the beaches of the world!
1
As these
lesions can block genome replication and transcription,
and if unrepaired or incorrectly rectified may result in
mutation or cell death, complex signaling networks
have evolved to carefully monitor the integrity of the
genome during DNA replication. These mechanisms
(collectively termed the DNA-damage response
[DDR]) detect DNA lesions, signal their presence and
promote their repair by the initiation of cell cycle arrest,
repair processes, or apoptotic responses.
2
e
4
It has taken a long time to achieve the current under-
standing of the DDR. Long before DNAwas recognized
as the basic repository of the genetic material of all life, it
was realized that environmental agents, such as X-rays,
induce mutations, and that cells have the innate ability
to recover from damage induced by UV light.
5
This led
to the recognition that cellular responses existed that
could cause a transient growth arrest allowing time
to repair the damage before resuming growth.
6,7
Studies
of DNA repair dominated the DDR field during the
1960s, 1970s, and 1980s, and provided a mechanistic
explanation for early observations, but it was not until
explorations of DNA damage signaling, cell cycle check-
points, and apoptosis led to the discovery of DNA
damage-induced signal transduction pathways during
the 1990s that the full extent of the DDR was better
appreciated. The DDR is now recognized to be a compre-
hensive and complex set of responses aimed at safe-
guarding the genomic integrity of cells.
8
DNA repair
processes lay the foundation of
sensors, signal trans-
ducers and effectors (
Figure 10.1
).
2
e
4
DNA damaging therapies are among the most
common cancer treatments and have produced signifi-
cant increases in the survival of patients, particularly
when used in combination with drugs with different
mechanisms of action. Although such therapies are
e
this response with
