Results reported in the April 2nd issue of the journal Cell, a Cell Press publication, reveal a new source for the drug resistance that crops up all too often and quickly in the tumors of cancer patients undergoing therapy. First the bad news: all cancer cells might have the capacity to enter a drug-tolerant state. But there's some potentially very good news too: in some cases there may be a way to reverse or block cancer's drug resistance.
"The problem with cancer drug therapy is that even the ones that work well generally only work for a limited time because drug resistance develops," said Jeff Settleman of Harvard's Massachusetts General Hospital Cancer Center.
Scientists have thought that resistance primarily stems from genetic causes - mutations in some tumor cells that may have pre-existed drug treatment. The theory holds that those drug-resistant mutants rise in prevalence with treatment as a classic example of survival of the fittest. "We're suggesting here that, while that may occur, there may be other non-genetic mechanisms [for drug resistance] that serve as a way to protect the tumor as a whole in a somewhat purposeful way," Settleman added.
While examining the acute response of human tumor cells in culture to various anti-cancer agents, Settleman and his colleague Marie Classon consistently detected a small subpopulation of reversibly "drug-tolerant" cells. Those cells were more than 100 times less sensitive to cancer drugs. They also found that the cells' drug tolerant state was transiently acquired and relinquished at low frequency by individual cells within the culture population.
The researchers don't yet know exactly how the cells manage that kind of reversible drug resistance, but they did uncover a couple of key features: the cells engage a signaling pathway including the IGF-1 receptor (which is a tyrosine kinase receptor) and their genetic material was also packaged differently into its three-dimensional structure (known as chromatin). That altered chromatin state depends on a particular enzyme that chemically modifies the histone proteins that are often likened to spools for DNA.
The new results add to other recent work suggesting that drug resistance might not always have to arise through genetic mutation, Settleman said. For example, accumulating evidence suggests that a small population of "cancer stem cells" is intrinsically more difficult to treat.
A handful of other studies have also raised the possibility that epigenetic mechanisms like the one now described might be at play, the researchers note. This path to reversible drug resistance may explain an increasingly observed phenomenon in cancer therapy -- the so-called "re-treatment response" in which cancer patients who have grown resistant to a variety of anticancer drugs can be successfully re-treated with the same drug after a "drug holiday."
The new study also suggests a promising new kind of combination cancer therapy designed to avoid drug resistance or as secondary treatment for cancers that have already developed resistance to other drugs. Indeed, the researchers found that their drug-tolerant cells in culture could be killed by treating them with IGF-1 receptor blockers or chromatin-modifying agents. "It presents a therapeutic opportunity," Classon said.
In fact, the researchers say they've already launched a clinical trial in patients with lung cancer to test a combination therapy including a chromatin-modifying agent and the drug erlotinib, which is a tyrosine kinase inhibitor.
"Although the trial is not yet completed, the early clinical data indicate that the inclusion of a chromatin-modifying agent can dramatically improve clinical benefit in a subset of patients demonstrating acquired tyrosine kinase inhibitor resistance," the researchers wrote in conclusion. "When considering that acquired drug resistance may involve multiple distinct molecular mechanisms that arise independently within the same patient, thereby complicating strategies to overcome such resistance with a single rationally targeted agent, the potential ability to prevent the development of resistance by disrupting a drug-tolerant state is provocative. However, further studies will certainly be required to establish the in vivo significance of the cell culture findings, as well as to determine more precisely the molecular mechanisms underlying reversible drug tolerance."
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