Biology Reference
In-Depth Information
therapeutic response. A summary of those findings
follows, listed by pathway.
MMR (Mismatch Repair)
In contrast to other pathways where a repair defi-
ciency represents a weakness to exploit, MMR defi-
ciency causes increased damage tolerance and striking
chemoresistance. Two avenues are currently being
researched for addressing MMR aberrations in tumor
cells:
DR (Direct Repair)
High expression of MGMT is associated with resis-
tance to alkylating agents. However, inhibition or low
expression of MGMT does not seem to exclusively guar-
antee greater efficacy of these anticancer agents, as the
BER and MMR pathways can repair such lesions as
well. Repair efficiency is also predicated on when in
the cell cycle the alkylated base is inserted, and whether
that timing leads to double-strand breaks. And,
although we know that specific methylation patterns
of
MGMT
can cause loss of gene expression, ongoing
studies are still inconclusive as to whether that might
be a predictive factor for aggressiveness of tumor
growth (see Chapter 2). Thus, the simplest repair
pathway still holds many clinical secrets regarding
DNA repair, crosstalk, and the prognostic value of
altered gene expression.
Hypomethylation of the hMLH1 gene promoter can
restore MMR function, which can make cells sensitive
to various chemotherapeutic agents.
Methotrexate has been shown to induce oxidative
DNA damage in tumor cells with defects in
MSH2.
Research to date indicates that an increased 8-oxoG
accumulation creates a synthetic lethality in cells
deficient in MLH1 or MSH2.
HR (Homologous Repair)
While PARP inhibition is a stunning example of how
a deficiency in HR can be turned into a synthetic
lethality in a germ line cancer, little is currently known
about the functionality of HR in most sporadic cancers.
This is complicated by the fact that chemotherapeutic
agents generally do not produce only one kind of lesion.
Furthermore, although HR activities are necessary to
repair that damage during and after replication, those
activities are complex
BER (Base Excision Repair)
Some of the most prevalent DNA lesions are a result
of alkylation and oxidation of its bases (Chapter 3). BER
is the primary means for removing base damage to
avoid mispairing or breaks during replication that could
cause mutations.
18
Because the intermediates produced
during DNA repair are more cytotoxic than the lesions
themselves, repair must proceed quickly, efficiently,
and accurately.
19
Over- or underexpression of certain
BER proteins can help determine sensitivity to radio-
therapy or chemotherapy:
involving many HR proteins
that have not yet been characterized. Thus, with the
exception of PARP/BRCA, it is difficult to point to
particular HR genes, their upstream regulators or medi-
ators, or clinically relevant SNPs as indicators of sensi-
tivity to radiotherapy or chemotherapy. Similarly,
demonstrated tumorigenic genome instability does not
necessarily equate to tumor sensitivity to particular anti-
cancer treatments. Therefore, testing the status of a single
HR gene, such as BRCA1, may not accurately convey HR
activity in a given tumor. A better measure of function-
ality would be to look for altered gene expression along
with compensatory mechanisms
e
Overexpression of Pol
b
is mutagenic and confers
a radiosensitive phenotype.
20
Deficiency of XRCC1, a BER scaffolding protein,
causes hypersensitivity to alkylating agents and IR.
21
Downregulation of NEIL1 increases radiosensitivity.
1
Upregulation of Ogg1 increases radiosensitivity.
1
although it still may
not be able to reflect the multitude of post-translational
modifications that also occur.
Some preclinical evidence indicates that IR may be
more effective in HR-deficient tumors than in HR-profi-
cient tumors, though more studies must be done to
provide additional clinical support for this. But that
finding comes with a caveat: hypoxic cells are up to
three times as radioresistant as well-oxygenated cells,
even though hypoxic cells have impaired HR function.
e
APE-1 overexpression is predictive of
chemotherapeutic resistance.
1
NER (Nucleotide Excision Repair)
The NER pathway responds to various kinds of helix-
distorting DNA damage. The versatility of NER repair
requires the coordination of more than 30 proteins, but
only a few to date seem to help predict response to
chemotherapy or radiotherapy:
Decreased expression of ERCC1 is associated with
better outcomes after cisplatin therapy.
22
NHEJ (Non-Homologous End Joining)
The NHEJ pathway is something of a paradox. While
it is the more frequently used method of DSB repair, it is
Inhibition of RPA confers radiosensitivity; it also
confers chemosensitivity to cisplatin and etoposide.
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