Biology Reference
In-Depth Information
2. A F
OCUS ON
ATR
Recently, a synthetic lethal interaction between
p53
and
ATR
, the upstream
activator of Chk1, has been described using a genetic model system in which a
human cancer cell line was modified to carry one of the
ATR
mutations known
to cause Seckel syndrome.
75
This mutation results in severely decreased levels
of ATR expression due to aberrant splicing.
15,76,77
Cells with defective levels of
ATR signaling showed a highly increased sensitivity to many DNA-damaging
agents and antimetabolites.
78
The authors of this study demonstrated that loss
of ATR expression selectively enhanced the response of
p53
-deficient cells to
treatment with the DNA-cross-linking agent cisplatin. In contrast, restoration
of p53 function in these ATR-deficient cells suppressed treatment-dependent
apoptosis, similar to the chemoprotective effect that was independently observed
in cells with functional p53 signaling in an ATM-deficient background.
79
Using a cell-based high-throughput screen in which inhibition of replica-
tion stress was used as a readout for ATR activity, Toledo and colleagues
recently identified two potent compounds that abrogate ATR signaling in the
nanomolar range.
80
One of these compounds, NVP-BEZ235, had previously
been recognized as a dual inhibitor of phosphatidylinositol-3-OH-kinase
(PI3K) and mTOR, and is currently being tested in the context of anticancer
therapy in clinical trials.
81
Another screen led to the identification of VE-821, a
novel compound with strong selectivity for ATR and little cross-reactivity
toward other PI(3)K-like kinases including mTOR.
82,83
Tests for the synergy
of ATR inhibition in combination with DNA-damaging therapy in a panel of
normal and cancer cell lines revealed that the combinatorial treatment was
most effective in inducing apoptosis in the context of ATM or p53 deficiency.
To date, no data related to the inhibition of ATR in combination with DNA-
damaging agents in mouse models of cancer have been published. However, a
recent study focusing on the suppression of ATR in the context of oncogenic
Ras transformation
84
highlights the importance of this signaling pathway in
the maintenance of genomic stability and raises important concerns about the
possible dangers of the use of ATR/Chk1-inhibiting compounds in the clinic. The
phenotypic outcome of ATR suppression in the used model systems was highly
dose-dependent: haploinsufficiency of
ATR
promoted oncogenic Ras-induced
tumorigenesis in
p53
-heterozygous knockout mice due to increased genomic
instability. However, abrogation of ATR signaling in cell lines expressing onco-
genic Ras increased genomic instability to intolerable levels, resulting in sup-
pressed proliferation and mitotic catastrophe. Haploinsufficiency-induced
tumorigenesis has also been described for
Chk1
-heterozygous mice in a breast
cancer model,
85
further elevating concerns about the therapeutic value of ATR/
Chk1 inhibitors in cancer patients. Consistent with this, human mutations or
suppression of the ATR/Chk1 pathway has been linked to different tumor
