There are many different strategies by which cancers can evolve resistance to anticancer drugs. Often, a cancer will be dramatically reduced in size by an initial drug treatment, with all of the detectable tumor cells seeming to disappear. But months or years later the cancer will reappear in an altered form that is resistant to the drug that was at first so successful. In such cases, the initial drug treatment has evidently failed to destroy some tiny fraction of cells in the original tumor-cell population. These cells have escaped death because they carry a protective mutation or epigenetic change, or perhaps simply because they were lurking in a protected environment. They eventually regenerate the cancer by continuing to proliferate, mutating and evolving still further as they do so.
In some cases, cells that are exposed to one anticancer drug evolve a resistance not only to that drug but also to other drugs to which they have never been exposed. This phenomenon of multidrug resistance frequently correlates with amplification of a part of the genome that contains a gene called Mdr1 or Abcb1. This gene encodes a plasma-membrane-bound transport ATPase of the ABC transporter superfamily (discussed in Chapter 11), which pumps lipophilic drugs out of the cell (see Movie 11.5). The overproduction of this protein (or some of its other family members) by a cancer cell can prevent the intracellular accumulation of many cytotoxic drugs, making the cell insensitive to them.
In the to-and-fro struggle between advanced metastatic cancer and the therapist, as current practice stands, the cancer usually wins in the end. Does it have to be so? As we discuss below, there is reason to think that by attacking a cancer with many weapons at once—instead of using them one after another, each until it fails—it may be possible to do much better.
Combination Therapies May Succeed Where Treatments with  One Drug at a Time Fail
Nowadays, cancers caught at an early stage can often be cured, by surgery, radiation, or drugs. For most cancers that have progressed and metastasized widely, however, cure is still beyond us. Treatments such as those described above can no cell is resistant CANCER CURED = cell resistant to Ato both drugs = cell resistant to A and B (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. 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.