Biology Reference
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of cells. The combined status of ATM and p53 was found to be a key determi-
nant for survival of patients after treatment: patients with tumors that were
deficient for either ATM or p53 alone had a significantly reduced survival
compared to patients with p53- and ATM-proficient tumors. Moreover, when
tumors had lost ATM in the presence of functional p53, those patients had the
poorest prognosis despite equivalent therapy. In contrast, patients with tumors
that had lost both ATM and p53 had a strikingly increased survival, although
the combination of these two mutations was highly underrepresented.
79
These
results again highlight that loss of ATM or p53 in isolation promotes resistance
against chemotherapy, while their combined loss or inactivation leads to in-
creased chemosensitivity (
Fig. 3
).
C. Sensitizing Chemo-Resistant Tumors that Have p53
Function: A Role for DNA-PKcs
The data discussed suggest that inhibition of ATM or Chk2 in a
p53-deficient background is a powerful method for sensitizing tumors to
DNA-damaging therapy by synthetic lethality. However, targeting of ATM in
a p53 wild-type setting causes exactly the opposite phenotype, conferring
therapeutic resistance, a phenomenon that was reflected in the decreased
patient survival. These data raised the possibility that loss of ATM in a p53-
deficient background might lead to new potentially synthetic lethal interaction
in the resistant tumors that could be used to kill these cells more efficiently by
DNA-damaging therapy. Indeed,
the blunted response to chemotherapy
in p53-deficient cancer cells. This redirecting of DNA damage-induced ATM signaling promotes
cellular survival in response to DNA damage. Treatment of p53-deficient tumors should include a
combination of conventional DNA-damaging chemotherapeutics and ATM inhibitors. (C) Loss of
ATM reduces the induction of the proapoptotic p53 target genes
Puma
and
Noxa
following DNA
damage. However, induction of cell cycle-regulatory p53 target genes such as
p21
or
Gadd45
a
remains intact, allowing ATM-deficient cancer cells to have enhanced cell cycle arrest after
genotoxic stress. As these cells are not dead, they can continue to proliferate once the DNA damage
is resolved. These tumors, however, depend on the DNA-PKcs-mediated nonhomologous end-
joining (NHEJ) pathway to repair chemotherapy-induced DSBs and maintain genomic stability.
Abolishing DNA-PKcs signaling in ATM-deficient cells leads to a strong increase in sensitivity to
DNA-damaging chemotherapy. Treatment of ATM-depleted tumors with retained p53 function
should include a combination of conventional DNA-damaging chemotherapy and DNA-PKcs
inhibitors. (D) Cancer cells with a combined loss of p53 and ATM lack functional cell cycle
checkpoints in response to genotoxic stress. This inability to stop progression through the cell
cycle despite the presence of DNA damage ultimately results in mitotic catastrophe. p53- and
ATM-deficient cancer cells should be exquisitely sensitive to treatment with conventional DNA-
damaging chemotherapy. However, these cells are likely to be deselected during tumor evolution as
a consequence of their presumed sensitivity to oncogene-induced replication stress (modified from
Ref.
37
).
