Biology Reference
In-Depth Information
2. DISRUPTING PROFICIENT HRR PATHWAYS
IN TUMORS THAT, IN CONTRAST TO NORMAL
TISSUES, ARE ACTIVATED, FOR EXAMPLE DUE TO
DEFECTS IN OTHER REPAIR PATHWAYS OR DUE TO
THE STIMULATORY EFFECTS OF ONCOGENIC
PATHWAYS
Therapeutic gain may be achieved by disrupting
oncogenic signaling that drives HRR and that is only
present in the tumor but not in normal tissues, an
example being the use of imatinib against tumors
with HRR driven by the BCR/ABL oncogene. An alter-
native concept would be the combination of IR with an
HRR inhibiting agent in tumors that carry mutations in
polymerase
b
. In order to achieve therapeutic gain, the
dose of the HRR inhibitor would have to be chosen low
enough so that damage to proliferating normal tissues
is minimized while any disruption of the already
strained HRR machinery in the tumor will produce
relatively tumor-specific cell kill. Theoretically,
elevated HRR levels as a result of p53 mutations in
tumors also offers a therapeutic window; however, to
which extent p53-dependent HRR affects cellular sensi-
tivity to DNA damaging agents is not well established.
Thus, all of these concepts necessitate a targetable alter-
ation that is present in tumor but not normal cells, and
therapeutic gain is achieved despite proficient HRR
pathways.
4. EXPLOITING DEFICIENT HRR IN TUMORS
ARISING IN PATIENTS WITH A GERM LINE
MUTATION IN A HRR GENE
While the same concepts of tumor cell kill apply as in
the paragraph above, the question arises whether
carriers of germ line mutations such as BRCA1 or
BRCA2 or even of single nucleotide polymorphisms in
an HRR gene are at increased risk of normal tissue injury
due to accumulation of unrepaired DNA damage. Thus
far, this does not seem to be the case though more study
is certainly needed.
Importantly, successful targeting of HRR in cancer
requires the identification of predictive biomarkers so
that only patients who are most likely to benefit will
receive a given treatment regimen.
Biomarkers of HRR Function and Treatment
Response
Network-Like Complexity of the DDR and HRR
DNA damage elicits a host of coordinated cellular
responses, including recognition of the lesion, cell cycle
arrest and chromatin de-condensation to allow for
repair, removal of the damage, and resumption of cell
proliferation. Alternatively, depending on the extent
of damage and the cell of origin, cells may be prevented
from re-entering cell cycle progression, for example by
undergoing apoptosis, necrosis, or senescence. Cellular
responses triggered by DNA damage are collectively
defined as the DDR (DNA Damage Response), as
described above. It has been recognized for many years
that these DDR pathways do not represent linear
sequences of events but involve complex networks
that include signaling cascades and feedback loops,
intricately linking cell cycle control, DNA repair, and
determination of cell fate.
130,366
Thus, it is not
surprising that many regulator and mediator proteins,
such as BRCA1 or p53, appear to have pleiotropic func-
tions in the response to genotoxic stress. Accordingly,
they are components of multiple protein machines,
which form at specific DNA damage sites. These
machines represent sets of probably dozens of spatially
positioned interacting proteins that undergo highly
ordered movements in a machine-like assembly.
366
When sets of proteins that can function either in repli-
cation, recombination, or repair processes assemble, it
is crucial that their activities are highly regulated and
applied only when and where they are needed. Thus,
the multiprotein complexes that form in response to
damaged DNA represent dynamic entities both in
time and in subnuclear location. Over recent years,
we have begun to more and more understand the
complexity of how DDR proteins are regulated via
intricate post-translational regulations,
367,368
3. EXPLOITING DEFICIENT HRR THAT IS PRESENT
IN TUMORS BUT NOT IN NORMAL TISSUES
This is expected to be the main opportunity for ther-
apeutic gain given the emerging evidence for disrupted
HRR pathways in a substantial fraction of human
cancers. This is perhaps best exemplified by the rapidly
spreading clinical testing of PARP inhibitors, which in
monotherapy cause synthetic lethality when treating
HRR-deficient tumors, yet are relatively non-toxic (see
Chapter 4). Tumor kill can be further enhanced by
combining PARP inhibitors with agents causing DNA
lesions that are substrates for the already defective
HRR machinery in the tumor. However, any combina-
tion therapy is expected to also increase normal tissue
toxicity. A second therapy concept involves the override
of cell cycle checkpoints that are activated by the accu-
mulation of DNA damage in HRR-deficient tumor cells.
The most promising class of inhibitors in this regard is
Chk1 kinase inhibitors. Additional therapeutic gain is
derived from
in vitro
and
in vivo
observations indicating
that cell kill is enhanced in tumors with mutant p53.
Normal cells that harbor wild-type p53 and have an
intact damage-induced G1/S checkpoint are relatively
spared. On the other hand, even a small reduction in
Chk1 levels in normal tissues could have undesirable
outcomes such as cancer development.
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such as
