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

1140 Chapter 20: Cancer
TREAT WITH
DRUG A
(A)
rare mutant cell,
resistant to drug A,
forms tumor
TREAT WITH
DRUG B
rare mutant cell,
resistant to drug B,
forms tumor
UNCONTROLLABLE
CANCER RESISTANT
TO BOTH DRUGS
Figure 20–46 Why multidrug treatments
can be more effective than sequential
treatments for cancer therapy.
(A) Because tumor cells are hypermutable,
two single-drug treatments that are given
sequentially often allow for the selection of
mutant cell clones that are resistant to both
drugs. (B) Simultaneous treatment with
both drugs can be more effective.
SIMULTANEOUS
TREATMENT WITH
BOTH DRUGS A AND B
(B)
no cell is resistant
to both drugs
CANCER CURED
KEY:
= cell sensitive to A and B
= cell resistant to A
= cell resistant to A and B
give valuable remissions, but sooner or later these are typically followed by relapse.
Nevertheless, for some relatively rare forms of advanced cancer, curative therapies
have been developed. These generally involve a cocktail of several different
anticancer agents: by trial and error, certain combinations of cytotoxic drugs have
been found to wipe out the cancer completely. MBoC6 m20.53/20.46 Discovering such combinations
has hitherto involved a long, hard search. But now, armed with our new tools for
identifying the specific genetic lesions that cancer cells contain, the prospects are
better.
The logic of combination therapies is the same as that behind the current treatment
of HIV-AIDS with a cocktail of three different protease inhibitors: whereas
there may always be some cells in the initial population carrying the rare mutations
that confer resistance to any one drug treatment, there should be no cell
carrying the whole set of rare mutations that would confer resistance to several
different drugs delivered simultaneously. In contrast, sequential drug treatments
will allow the few cells resistant to the first drug to multiply to large numbers.
Within this large population of cells resistant to the first drug, a small number
of cells are likely to have arisen that are resistant to the next drug also; and so on
(Figure 20–46).
We Now Have the Tools to Devise Combination Therapies
Tailored to the Individual Patient
Efficient, rational combination drug therapy requires three things. First, we have
to identify multiple peculiarities of cancer cells that make them vulnerable in ways
that normal cells are not. Second, we have to devise drugs (or other treatments)
that target each of these vulnerabilities. Third, we have to match the combination
of drugs to the specific set of peculiarities present in the cancer cells of the individual
patient.
The first requirement is already partially met: we now have large catalogs of
cancer-critical genes that are commonly mutated in cancer cells. The second
requirement is harder, but attainable: we have described some remarkable recent
successes, and for cancer researchers there is excitement in the air. It is becoming
increasingly possible to use our growing knowledge of cell and molecular biology
to design new drugs against designated targets. At the same time, efficient,
high-throughput automated methods are available to screen large libraries of
chemicals for any that may be effective against cells with a given cancer-related
defect. In such searches, the goal is synthetic lethality: a cell death that occurs
when and only when a particular drug is put together with a particular cancer
cell abnormality. Through these and other approaches, the repertoire of precisely
targeted anticancer drugs is rapidly increasing.