Sensitivity, resistance of tumor cells to chemo linked to genetic abnormality

Researchers at Dana-Farber Cancer Institute and a team of international collaborators have identified a genetic abnormality that makes ovarian tumor cells initially sensitive to a common chemotherapy agent, cisplatin, and then resistant to the drug over time.
From Dana-Farber Cancer Institute:Sensitivity – then resistance – of some ovarian tumor cells to chemotherapy linked to genetic abnormality

Researchers at Dana-Farber Cancer Institute and a team of international collaborators have identified a genetic abnormality that makes ovarian tumor cells initially sensitive to a common chemotherapy agent, cisplatin, and then resistant to the drug over time.

Published in the May issue of Nature Medicine, the study challenges conventional thinking about how cancer cells are able to “outsmart” therapies that at first are effective against them.

“It has been thought that as normal cells evolve into cancerous ones, they acquire more and more genetic damage – to the point where they gain the ability to withstand drugs that once killed them,” says the study’s senior author, Alan D’Andrea, MD, of Dana-Farber and Children’s Hospital Boston. “While that may indeed take place, our study points to another possibility: that cancer cells can, in effect, ‘go backward,’ switching some genes to a normal state so they essentially disguise themselves from common therapeutic agents.”

The finding represents both a hurdle to the development of new anti-cancer drugs and, paradoxically, a crucial step toward the discovery of such drugs. Scientists working on drug development now know that they are chasing more of a moving target than they may have realized. They also have a better sense, however, of how to counter these cellular shifts.

The new study stems from D’Andrea’s research in Fanconi anemia, an inherited condition that places children at risk for bone marrow failure early in life and various forms of cancer as they get older. The disease is caused by a defect, or mutation, in any of seven genes that act as a tag-team to repair damaged DNA. Over the last few years, D’Andrea and his colleagues found that this gene “pathway” leads directly to BRCA1 and BRCA2, two of the best known cancer genes in human cells. When either of the BRCA genes or any of those in the Fanconi pathway are mutated, the result can be breast cancer, ovarian cancer, or any of a variety of other malignancies.

When the Fanconi-BRCA pathway doesn’t function properly, the DNA in ovarian cells tends to snap and recombine in abnormal ways. This causes the cells to become cancerous, but it also makes them highly susceptible to cisplatin.

“Cisplatin has been a front-line chemotherapy drug for ovarian and other cancers for decades,” explains the study’s first author, Toshiyasu Taniguchi, MD, PhD, a pediatric oncologist at Dana-Farber and Children’s Hospital. “It’s one of the more selective agents in our arsenal: it kills cancer cells effectively but doesn’t do a great deal of harm to normal tissue.”

Unfortunately, that effect is rarely lasting. Over time, ovarian tumors tend to become resistant to cisplatin and resume their malignant growth.

From scientists’ point of view, this vulnerability is a kind of happy accident: they know cisplatin works, but they don’t know – at the basic level of genes and proteins – why; nor do they know why it eventually loses its potency.

To find out, Taniguchi and his colleagues examined the Fanconi-BRCA pathway in ovarian tumor cells that are vulnerable to cisplatin. As expected, they found the pathway wasn’t working properly, but they were startled to discover that all of its genes were structurally normal. “We’d thought at least one of them would be mutated,” Taniguchi states. “That would have been the obvious explanation for the pathway’s disruption. But, clearly, something else was to blame.”

That ‘something’ turned out to be a process known as “gene silencing.” It occurs when compounds known as a methyl groups wrap themselves around a gene. The impact is akin to stifling a trumpet with a rubber seal: the gene stays perfectly intact, but it cannot function until the methyl group is removed.

With the gene smothered by methyl groups and the Fanconi-BRCA pathway disabled, the cell undergoes two types of changes. It breaks free of its normal, orderly growth routine and begins to show signs of malignancy. At the same time, it develops a vulnerability to cisplatin.

“The sensitivity to cisplatin can be seen as the price the cell pays for becoming cancerous,” remarks D’Andrea, who is also a professor of pediatrics at Harvard Medical School. “Even as the cell becomes more aggressive, it gains a new weak spot.”

Unfortunately, that weak spot doesn’t last forever. Cancer cells often “learn” how to reverse the gene-silencing process. By stripping methyl groups from the gene, they re-activate the Fanconi-BRCA pathway, rendering themselves invincible to cisplatin. At the same time, though, they retain many of the harmful gene mutations acquired during their wild, rapid-growth days. They become cancer cells resistant to cisplatin.

The discovery deepens scientists’ understanding of the process of drug resistance and should instill a new appreciation for cancer’s drug-dodging capacity, D’Andrea notes. At the same time, it suggests a new strategy for fighting the disease. Because researchers now know a cause of cisplatin resistance in ovarian cancers, they may be able to devise ways of reversing the process and “re-sensitizing” tumors to the drug.

Co-authors of the study included researchers at Brigham and Women’s Hospital, Guy’s King’s and St. Thomas’ School of Medicine in London, and VU University Medical Center in Amsterdam, the Netherlands.

The study was funded in part by grants from the National Institutes of Health and the Doris Duke Charitable Foundation.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.


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