Biology Reference
In-Depth Information
Furthermore, several kinase inhibitors against these path-
ways have been developed and entered clinical trials.
pathway, though presumably at the cost of an increased
rate of mutations and genomic instability.
348
ATM inhib-
itors have been developed and undergone extensive
laboratory testing, with the most commonly used agent
being probably KU55933 (AstraZeneca). Inhibition of
ATMkinase functionwill have pleiotropic cellular effects
due to the large number of ATM substrates.
353
With
regard to disrupting ATM-dependent HRR, ATM has
been reported to regulate HRR of DSB in the G2 phase
of the cell cycle and also has a poorly defined function
in response to replication fork collapse.
90,313,354
Thus, dis-
rupting ATM function would be expected to sensitize
cancer cells to PARP inhibition, as recently shown for
lymphoid tumor cells (see also Chapter 4).
355
However,
it is difficult to envision at the current time how ATM
inhibitors would be preferentially toxic to tumors but
not to healthy normal tissues. Possibly, ATM inhibitors
may be useful against cancers with hyperactive ATM
due to increased DSB levels, for example in the context
of FA deficiency.
356
We are not aware of any current clin-
ical trials involving an ATM inhibitor.
Several of the Chk1 inhibitors have also activity
against Chk2.
348
Whether dual inhibition of both Chk1
and Chk2 is relevant to the effectiveness of the Chk1
inhibitors is unclear. Agents specifically targeting Chk2
are under development. Recently a novel Chk2 inhibitor,
CCT241533, was identified and conferred sensitization
to PARP inhibitors.
357
It remains to be determined
whether this effect is due to a cell cycle checkpoint func-
tion or an involvement in aspects of HRR, possibly
through BRCA1.
282
The efforts to exploit pre-existing HRR defects in
tumors or disrupt proficient HRR, as described above,
are in their infancy but hold great promise to broadly
impact cancer therapies in the next few years. As our
understanding of the regulation of HRR pathways in
normal and malignant cells deepens, additional rational
treatment strategies are likely to materialize. Novel
treatment approaches can only be successful in appro-
priately selected patients with correlative science to
ensure that HRR pathways are truly impacted or
exploited, and if applicable, resistance mechanisms are
identified and overcome.
ATR-Chk1 Inhibition
Somatic mutations in the ATR or Chk1 kinases are
rarely found in human cancers (reviewed in
348
). Bi-
allelic knock-out of ATR or Chk1 in mice is embryonic-
lethal, consistent with an essential role of these genes
in normal development, stem cell survival, and tissue
homeostasis. It can thus be inferred that in most human
cancers, ATR-Chk1 function is intact (though reduced
gene expression via epigenetic mechanisms cannot be
ruled out). Therefore, the ATR-Chk1 pathway becomes
a logical target for therapeutic strategies that involve
pharmacological inhibition. ATR-Chk1 inhibition is
expected to be particularly useful in several
settings:
242,348
(1) checkpoint disruption in HRR defi-
cient tumor cells with increased damage levels; (2)
reversal of enhanced DNA repair in radio-/and chemo-
resistant cancers, as ATR-Chk1 is known to promote
HRR;
56,349
(3) checkpoint override in p53-mutant tumor
cells that have lost the protective damage-induced G1/S
cell cycle checkpoint.
349,350
With regard to the latter
mechanism, as BRCA1-mutant breast cancers typically
also carry p53 mutations,
351
Chk1 inhibition should be
particularly effective in these cases.
With regard to inhibition of Chk1, a large body of
preclinical data with several inhibitors has accumulated
to demonstrate that this approach enhances the extent
and severity of DNA damage caused by various chemo-
therapeutics or radiation, thereby causing apoptosis or
premature entry into mitosis with unreplicated DNA
(reviewed in
348
). It has also been proposed that Chk1
inhibition in HRR-deficient tumor cells may cause
synthetic lethality even without exposure to chemother-
apeutics, analogous to the effects of PARP inhibition in
this setting.
242
While direct evidence for this principle
is still lacking, recent data from the D'Andrea laboratory
showed that cells with defects in the FA pathway hyper-
activate Chk1 and are thus sensitive to Chk1 inhibi-
tion.
352
In that study, the combination of Chk1 inhibition
and cisplatin treatment was synergistic in FA cells, sug-
gesting a benefit for this treatment combination in
patients whose tumors harbor alterations in the FA
pathway (or BRCA1/2 genes). Because Chk1 promotes
HRR inhibition, inhibition of Chk1 may also be advanta-
geous in HRR proficient tumors when combined with
agents producing DNA lesions that are substrates for
HRR. Several Chk1 inhibitors are undergoing clinical
testing (see
Table 7.3
). In contrast to Chk1, to our knowl-
edge no ATR inhibitor has yet been developed.
BIOMARKERS AND CLINICAL
TRANSLATION
Therapeutic Ratio
Early Versus Late Side Effects
The “therapeutic ratio” describes the balance between
tumor kill and injury to healthy normal tissues and
organs (
Figure 7.9
). All cancer therapies developed to
date are associated with a spectrum of early and late
ATM-Chk2 Inhibition
In contrast to the ATR-Chk1 pathway, cells can tolerate
partial or complete loss of functionwithin the ATM-Chk2
