A pair of new studies may reveal why some commonly used cancer drugs aren't as effective as expected in some patients.
The studies, one looking at leukemia cells and the other at cells from colon, ovarian and lung tumors, show that when a specific gene, called FBW7, is missing from the tumor or appears in a variant form, some of the drugs don't have their desired cell-killing effects.
The research also suggests an approach for treating such tumors.
"Our work can provide for a targeted therapy regimen," said study researcher Wenyi Wei, who worked on the leukemia findings.
The research appears in the most recent issue of Nature.
The researchers chose to study the role of FBW7 in leukemia because of the broad implications. Up to 30 percent of patients with T-cell acute lymphoblastic leukemia may have tumors with variants of FBW7, said Wei, an independent investigator at Beth Israel Deaconess Medical Center in Boston.
Both new studies suggest that without FBW7, cancer cells survive drug treatments because they have high levels of a protein called MCL1. Cells with normal FBW7 genes will break down MCL1 and die from the drugs.
"Cancer cells are very selfish," Wei said. "They want to grow forever. .. They don't need a lot of growth stimuli, and they are escaping cell death."
The drugs in question, which include taxol and ABT-737, stop cells from dividing. But high levels of MCL1 appear to allow cells, while not dividing, to live on and sometimes mutate — then resume dividing when the drugs' effects wear off.
"They not only escaped the cell death and don't die, but they're even more mutated and transformed than they were even before they saw the drug," said Dr. Ingrid Wertz, a researcher in the Department of Early Discovery Biochemistry at Genentech Inc., who worked on the research in colon, lung and ovarian cancer tumors. "It was sort of a double whammy."
"I think the quality of these papers is quite high, and the results are really interesting," said Dr. Bruce Clurman, a medical oncologist with the Fred Hutchinson Cancer Research Center in Seattle. "However, a lot more work is needed to ascertain how significant these findings will turn out to be with respect to treatment and prognosis."
Clurman said that new therapies might be targeted at reducing MCL1, but leukemia and lung cancer are likely to need different treatments. It also remains unclear whether any existing drugs could treat these tumors.
Wertz said that even if researchers were extraordinarily lucky to find a new drug to treat the tumors, it would not begin clinical trials for five years.
But Alex Almasan, a cancer biology researcher at the Cleveland Clinic who has studied FBW7, said the new studies give reason to be optimistic. In addition to elucidating a possible reason for the failure of current treatments, the studies present a target for future research.
Rather than use single drugs, "in the clinic, they use cocktails. This suggests it would be good to combine [chemotherapy drugs] with something that downgrades MCL1," Almasan said.
Further, he noted, high levels of MCL1 had previously been linked to worse outcomes in cancer treatment.
"This is huge," Almasan said. "Because now you have a reason why these cells aren't responsive."
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