Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CANCER PREVENTION AND TREATMENT: PRESENT AND FUTURE
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in a tumor have evolved to be unusually tolerant of minor DNA damage, they are
hypersensitive to the much greater amount of damage that can be created by radiation
and by DNA-damaging drugs. A small increase of genetic damage can be
enough to tip the balance between proliferation and death.
Unfortunately, while the molecular defects present in cancer cells often
enhance their sensitivity to cytotoxic agents, they can also increase their resistance.
For example, where a normal cell might die by apoptosis in response to
DNA damage, thanks to the stress response mediated by p53, a cancer cell may
escape apoptosis because its p53 is lacking. Cancers vary widely in their sensitivity
to cytotoxic treatments, some responding to one drug, some to another, probably
reflecting the particular kinds of defects that a particular cancer has in DNA
repair, cell-cycle checkpoints, and the control of apoptosis.
New Drugs Can Kill Cancer Cells Selectively by Targeting Specific
Mutations
Radiotherapy and traditional cytotoxic drugs are rather weakly selective: they hurt
normal cells as well as the cancer cells, and the safety margin is narrow. The dose
often cannot be raised high enough to kill all the cancer cells, because this would
kill the patient, and curative treatments, where achievable, generally require a
combination of several cytotoxic agents. The side effects can be harsh and hard to
endure. How can we do better?
An ideal treatment is one that is cell-lethal in combination with some lesion
that is present in the cancer cells, but harmless to cells where this lesion is absent.
Such a treatment is said to be synthetic-lethal (from the original sense of the word
synthesis, meaning “putting together”): it kills only in partnership with the cancer-specific
mutation. As we become increasingly able to pinpoint the specific
alterations in cancer cells that make them different from their normal neighbors,
new opportunities for such precisely targeted treatments are coming into view.
We end this chapter with some examples of new treatments of this type that are
already being put into practice.
PARP Inhibitors Kill Cancer Cells That Have Defects in Brca1 or
Brca2 Genes
As we have emphasized, the genetic instability of cancer cells makes the cells
both dangerous and vulnerable—dangerous because of the enhancement in their
ability to evolve and proliferate, and vulnerable because treatment that leads to
still more extreme genetic disruption can take them over the brink and kill them.
In some cancers, genetic instability results from an identified fault in one of the
many devices on which normal cells depend for DNA repair and maintenance.
In this case, a drug is tailored to block a complementary part of the DNA repair
machinery can lead to such severe genetic damage that the cancer cells die.
Detailed studies of the mechanisms for DNA maintenance discussed in Chapter
5 reveal a surprising amount of apparent redundancy. Thus, knocking out a
particular pathway for DNA repair is generally less disastrous than one might
expect, because alternate repair pathways exist. For example, stalled DNA replication
forks can arise when the fork encounters a single-strand break in a template
strand, but cells can avoid the disaster that would otherwise result either by
directly repairing these single-strand breaks, or, if that fails, repairing the broken
fork that results by homologous recombination (see Figure 5–50). Suppose that the
cells in a particular cancer have become genetically unstable by acquiring a mutation
that reduces their ability to repair broken replication forks by homologous
recombination. Might it be possible to eradicate that cancer by treating it with a
drug that inhibits the repair of single-strand breaks, thereby greatly increasing the
number of forks that break? The consequences of such drug treatment might be
expected to be relatively harmless for normal cells, but lethal for the cancer.
This strategy appears to work to kill the cells in at least one class of cancers—
those that have inactivated both copies of either their Brca1 or their Brca2 tumor