The capability of cancer cells to resist treatment with either targeted drug therapies or conventional chemotherapy, in a few cases, is derived from a brief condition of reversible drug ‘tolerance.’ Scientists from the Massachusetts General Hospital (MGH) Cancer Center seemed to account for discovering small populations of drug-tolerant cells from numerous diverse kinds of tumors and recognizing factors of the underlying mechanism.
When cells in a tumor that had reacted to treatment recommence unrestrained development, drug therapy is generally halted. But there have been many reports signifying that a few tumors may regain sensitivity to the formerly unsuccessful treatment following a ‘drug holiday’. In order to examine the mechanism underlying that happening, the researchers evaluated numerous tumor-derived cell lines against drugs to which the original tumors were recognized to be sensitive.
“While resistance to cancer drugs can result from rare, pre-existing genetic mutations that emerge in response to treatment, accumulating evidence has pointed to additional nongenetic, potentially reversible mechanisms. In cell lines derived from several different types of cancer we found subpopulations of cells that display a transient ability to tolerate exposure to toxic drugs, which was associated with structural changes in the cells’ DNA and points to a therapeutic strategy that could potentially prevent resistance from developing,” commented, Jeffrey Settleman, PhD, of the MGH Cancer Center, who headed the research.
In every line they checked, a minute amount of tumor cells appeared to survive exposure to concentrations of drug 100 times more as compared to levels that destroyed the enormous bulk of the cells. But when these drug-tolerant cells were positioned in a setting devoid of the drug, their offspring in due course regained sensitivity to the drug.
Additional examination divulged that drug tolerance appeared to be linked to alterations in gene expression, thereby implicating changes in chromatin. The study authors discovered that a certain chromatin-modifying enzyme was needed for the growth of tolerance. While no presently accessible drug restrains that protein, agents that obstruct a connected group of enzymes apparently did cause the death of drug-tolerant but not drug-sensitive cells.
Settleman mentioned, “We believe this kind of reversible drug resistance may be a fundamental property of many tumor cell populations. Determining whether what we see in cell cultures will translate into what happens in patients is essential, and we’ve already started a clinical trial to see if combining a chromatin-modifying agent with the targeted lung-cancer drug erlotinib [Tarceva] may prevent or delay the development of resistance.”
The researchers are apparently using their cell culture modes to further explore the underlying mechanisms.
The research was published in Cell.