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 continues, due to permanently suppressor genes. As described in Chapter 5, Brca2 is an accessory protein that interacts with the Rad51 protein (the RecA analog in humans) in the repair of DNA double-strand breaks by homologous recombination. Brca1 is another protein that is also required for this repair process. Like Rb, the Brca1 and Brca2 genes were discovered as mutations that predispose humans to cancer—in this case, chiefly cancers of the breast and ovaries (though unlike Rb, they seem to be involved in only a small proportion of such cancers). Individuals who inherit one mutant copy of Brca1 or Brca2 develop tumors that have inactivated the second copy of the same gene, presumably because this change makes the cells genetically unstable and speeds tumor progression.
While Brca1 and Brca2 are needed for the repair of DNA double-strand breaks, single-strand breaks are repaired by other machinery, involving an enzyme called PARP (polyADP-ribose polymerase). This understanding of the basic mechanisms of DNA repair led to a striking discovery: drugs that block PARP activity kill Brca-deficient cells with extraordinary selectivity. At the same time, PARP inhibition has very little effect on normal cells; in fact, mice that have been engineered to lack PARP1—the major PARP family member involved in DNA repair—remain healthy under laboratory conditions. This result suggests that, while the repair pathway requiring PARP provides a first line of defense against persistent breaks in a DNA strand, these breaks can be repaired efficiently by a genetic recombination pathway in normal cells. In contrast, tumor cells that have acquired their genetic instability by the loss of Brca1 or Brca2 have lost this second line of defense, and they are therefore uniquely sensitive to PARP inhibitors (Figure 20–41).
PARP inhibitors are still under clinical trial, but they have produced some striking results, causing tumors to regress in many Brca-deficient patients and delaying progression of their disease, with relatively few disagreeable side effects. These drugs also appear to be applicable to cancers with other mutations that cause defects in the cell’s homologous recombination machinery—a small, though significant, proportion of cancer cases.