Biology Reference
In-Depth Information
FIGURE 10.1
Components of the DNA damage response pathways modulated by Wee1 and Chk kinases.
in K562/A02 human erythroleukemic cell lines.
14
In
addition, glioma stem cells were shown to promote
radioresistance through activation of the checkpoint
pathway, thus targeting the checkpoint response in this
setting may overcome radioresistance and improve the
therapeutic outcome in malignant brain cancer.
15
Inhibitors against three of the key regulators of cell
cycle checkpoints, namely Chk1, Chk2 and Wee1, are
currently in clinical development, and these targets
and their inhibitors will be discussed in detail below.
associated with significant adverse side effects in normal
tissues, they are often efficacious and therefore DNA
damaging agents are likely to remain a standard of
care for the treatment of many cancers for the foresee-
able future (
Table 10. 1
). The majority of these agents
are used at the maximum tolerated dose (MTD). Toxic-
ities to the hematological, gastrointestinal and other
organ systems are commonly observed and limit the
dose that can be tolerated and the degree of tumor
control that can be achieved. The therapeutic window
that can be achieved with DNA-damaging therapies
relies on the fact that, in addition to proliferating much
more rapidly than normal tissue, most cancer cells
have impaired DDR as they have undergone an array
of genetic changes (including mutations in the DNA
repair pathways) to remove controls and barriers to
proliferation.
Nevertheless, DNA repair still provides a common
mechanism for cancer-therapy resistance, and several
recent advances have implicated checkpoint pathway
activation as a major mechanism driving both chemo-
and radioresistance. For example, the ATR-Chk1
pathway is strongly activated in BCR/ABL-positive
cells and this was shown to contribute to the resistance
of these cells to treatment with DNA cross-linking
agents.
13
Increased Chk1 activity has also been found
to be associated with cellular resistance to adriamycin
TARGETS FOR CHECKPOINT
ABROGATION
Checkpoint Kinases 1 and 2
DNA damage triggers recruitment of multi-protein
complexes (sensors) that then activate the transducers
ATM (ataxia telangiectesia mutated) and ATR (ATM
and Rad3 related). It is generally accepted that ATR acti-
vation is driven by single-strand breaks (SSBs) formed
as a result of stalled replication forks, whereas ATM is
the main initiator of response to double-strand breaks
(DSBs) resulting from ionizing radiation and other types
of DNA damage.
16
Once activated, ATM and ATR phos-
phorylate a host of substrates, initiating a cascade that
