The more complex and costly the mechanisms used, the less fit the resistant population will be. That cancer cells pay a price for resistance is supported by several observations. Cells in laboratory cultures that are resistant to chemotherapies typically lose their resistance when the chemicals are removed. Lung cancer cells that are resistant to the chemotherapy gemcitabine are less proliferative, invasive and motile than their drug-sensitive counterparts.
Although resistant forms are commonly found in tumors that haven’t yet been exposed to treatment, they generally occur in small numbers. This suggests that resistant cells are not so unfit that drug-sensitive cells completely out-competed them, but that they struggle to proliferate when both types are present.
Our models show that in the absence of therapy, cancer cells that haven’t evolved resistance will proliferate at the expense of the less-fit resistant cells. When a large number of sensitive cells are killed, say, by aggressive therapies, resistant types can proliferate unconstrained. This means that high doses of chemotherapy might actually increase the likelihood of a tumor becoming unresponsive to further therapy.
So, just as judicious use of pesticides can control invasive species, a therapeutic strategy designed to maintain a stable, tolerable tumor volume could improve a patient’s prospects for survival by allowing sensitive cells to suppress the growth of resistant ones.
To test this idea, we treated a human ovarian cancer, grown in mice, with conventional high-dose chemotherapy. The cancer rapidly regressed but then recurred and killed the mice. Yet when we treated the mice with a drug dose continuously adjusted to maintain a stable tumor volume, the animals, though not cured, survived for a prolonged period of time.
Designing therapies to sustain a stable tumor mass rather than eradicate all cancer cells will require a strategy that looks beyond the immediate cytotoxic effects of any one treatment. Researchers will need to establish the mechanisms by which cancer cells achieve resistance and what it costs them. They will need to understand the evolutionary dynamics of resistant populations, and design strategies to suppress or exploit the adapted characteristics.
Of course, cancer researchers should not abandon their search for ever-more-effective cancer therapies, even for cures. But it may be time to temper our quest for magic bullets and recognize the cold reality of Darwin’s evolutionary dynamics. Medicine’s goal of a glorious victory over cancer may need to yield to our recognizing that an uneasy stalemate may be the best that can be achieved.
Robert Gatenby is chairman of radiology and integrated mathematical oncology at the H. Lee Moffitt Cancer Center.
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