Discoveries
Dana-Farber study challenges conventional wisdom about the causes of drug resistance by tumors
A recent study shows that cancer cells are capable of doing a genetic do-si-do, reversing the very abnormalities that initially make them vulnerable to chemotherapy.
Toshiyasu Taniguchi, MD, (front) and Alan D'Andrea, MD, are probing the ability of tumors to resist drugs.
The research, led by DFCI's Alan D'Andrea, MD, and Toshiyasu Taniguchi, MD, provides a new explanation for the common but frustrating occurrence of drug resistance, in which tumors become able to withstand medications that had once caused them to shrivel.
The study, which involved ovary cells, stems from years of investigations into Fanconi anemia, a rare, inherited condition that puts children at risk for bone marrow failure and cancer. D'Andrea, Taniguchi, and their colleagues had previously discovered that the genes involved in the disease form a "pathway" that activates BRCA1 and BRCA2, two of the best-known cancer genes in human cells. When the Fanconi-BRCA pathway doesn't function properly, the chromosomes in ovarian cells tend to snap and recombine in abnormal ways. This can cause the cells to become cancerous, but it also makes them highly susceptible to a chemotherapy agent called cisplatin. That susceptibility, however, is rarely permanent.
To understand why, the investigators examined the Fanconi-BRCA pathway in ovarian tumor cells that were vulnerable to cisplatin. They found that although all the genes in the pathway were structurally normal, some had been "silenced" by the binding of certain molecules. The disruption can force cells to begin growing out of control — that is, to turn cancerous — while at the same time becoming susceptible to cisplatin.
Unfortunately, cells often develop a resistance to the drug. By reversing the silencing process and reactivating the Fanconi-BRCA circuit, they gain the ability to prevail against a cisplatin attack. At the same time, they retain many of the other harmful gene mutations they had already acquired, making them cisplatin-resistant cancer cells.
"The study points to the 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," D'Andrea says. Researchers hope the discovery will lead to new strategies for "rensensitizing" tumors to cancer drugs.
