Biology Reference
In-Depth Information
The acquired mutations often affect a subset of conserved pathways, including
DNA damage repair and cell cycle control, in addition to apoptosis, integrin
signaling, regulation of cell adhesion and invasion, small GTPase-dependent
signaling, TGF
-signaling, Wnt/Notch signaling, and Hedgehog signaling.
6
As these pathways become rewired and subject to new mechanisms of regula-
tion, they become promising targets for anticancer therapy.
Some of the critical ''driving'' genetic lesions within these oncogenic sig-
naling pathways can be targeted with small molecules. Inhibition of mutant or
amplified ErbB receptors (Erlotinib, Gefitinib, Trastuzumab)
7,8
or BCR-Abl
(Imatinib),
9
for example, is among the most successful strategies for targeting
critical signaling components in cancer cells. Other classes of oncogenes,
especially nonkinases such as Myc or Ras, have proven to be less ''drug-
gable.''
10,11
In addition, therapeutic restoration of commonly lost tumor
suppressor genes, including
p53, Rb, BRCA1/2, p16
INK4A
,
and
ATM
, has not
yet become a feasible option for anticancer therapy. Importantly, many of these
genes play a role in the DNA damage response and DNA repair pathways,
which are among the most frequently compromised networks in human can-
cers.
12-20
Therefore, targeting oncogenic signaling pathways in combination
with DNA damage treatments may offer improved efficacy compared to
treatment with pathway inhibitors alone.
b
B. The DNA Damage Response
In response to DNA damage, cells activate complex signaling networks that
mediate DNA repair and cell cycle arrest, or if the damage is extensive, they trigger
apoptosis
2,21
(
Fig. 1
A). The DNA damage response is initiated by the activation of
the PI(3)K (phosphatidylinositol-3-OH-kinase)-like kinases ATM (ataxia telangiec-
tasia mutated), ATR (ATM and Rad related), and DNA-PKcs (DNA-dependent
protein kinase catalytic subunit). These kinases recruit repair machinery directly to
sites of DNA damage while also halting progression through the cell cycle by
activating the effector kinases Chk2 and Chk1.
22-24
While the ATM/Chk2 pathway
responds primarily to DNA double-strand breaks (DSBs), the ATR/Chk1 module
is activated by exposure of DNA single strands at breaks or sites of bulky DNA
base adducts. Recently, we have identified the stress-activated p38MAPK/MK2
(MAPKAPK2) pathway as a third checkpoint regulator that is activated down-
stream of ATM and ATR upon DNA damage.
25,26
The networks regulated by
these checkpoint effector kinases affect a variety of cellular outcomes including
cell cycle arrest, DNA repair, chromatin assembly, transcriptional and posttran-
scriptional regulation of gene expression, and cell death
2,27
(
Fig. 1
A).
The activation of ATM/ATR-Chk1/Chk2/MK2-controlled checkpoints
leads to a delay in cell cycle progression through the G1, S, or G2 phase
(
Fig. 1
B). The transcription factor p53 is a major effector of DNA kinase
pathways
28
and mediates arrest in G1 mainly through the upregulation of
