March 14, 2011

Faulty Gene Helps Tumors Dodge Drugs

Electron microscope image showing a cluster of misshapen cells A cluster of breast cancer cells.Annie Cavanagh. All rights reserved by Wellcome Images.

Two research teams have shown how a defective or missing gene may allow some tumors to resist cancer-fighting drugs. The finding may aid new drug development and eventually lead to more targeted chemotherapy based on patients’ genes.

The gene, FBW7, was already known to play some role in helping to keep cancer at bay. Scientists had found that FBW7 was missing or altered in certain types of cancer, including leukemia, breast cancer and colon cancer. But its mechanism of action had been unclear.

In the new studies, 2 independent scientific teams used different approaches and studied different types of cancer to uncover details of how the FBW7 protein keeps cell growth in check — and how missing or malfunctioning FBW7 can help tumors become drug resistant. Their results were reported in separate papers in the March 3, 2011, issue of Nature.

In one study, Dr. Wenyi Wei of Beth Israel Deaconess Medical Center in Boston and his colleagues focused on T-cell acute lymphoblastic leukemia, a cancer of the blood and bone marrow. Up to one-third of patients with this type of leukemia lack normal FBW7. The scientists also analyzed the protein MCL1, which is known to be over-produced in some types of leukemia. High levels of MCL1 can protect cells from apoptosis, or cell death. Their research was funded in part by NIH’s National Institute of General Medical Sciences (NIGMS).

In a series of experiments, the scientists found that FBW7 normally tags the MCL1 protein for destruction, which helps to keep its levels in check. But when FBW7 is missing, levels of MCL1 rise, protecting cells from death.

The researchers also found that FBW7-deficient leukemia cells are readily destroyed by an anti-cancer drug that decreases MCL1 levels (sorafenib). "We showed that if you specifically reduce MCL1 in FBW7-deficient cells, the cells will undergo apoptosis more easily than normal cells," Wei says.

In contrast, the FBW7-deficient cells were resistant to a different family of cancer-fighting drugs called BCL2 inhibitors. The inhibitors worked effectively only in cells with normal FBW7 or depleted MCL1. The findings suggest that testing patients for variations in either of these genes might point to the best class of drug for that individual.

In the second study, Dr. Ingrid Wertz of Genentech in San Francisco and her colleagues focused on certain widely prescribed anti-cancer drugs, including Taxol and vincristine. These drugs block cancer growth by binding to the tubulin proteins needed for cell division. In research partly supported by NIH’s National Cancer Institute (NCI), the scientists reported that response to these drugs is largely determined by MCL1 and FBW7 levels in ovarian and colon cancer cells. Their findings suggest that testing tumor cells for levels of these proteins could help to predict patient response to antitubulin agents.

"Screening for FBW7 is an easy thing to do, and it lets us predict who's likely to respond to certain drugs and who won't respond at all," says Wei. "These studies basically offer a rationale for targeted therapy."

— by Vicki Contie

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