By Cassandra Willyard
Potent chemotherapy drugs such as Taxol (paclitaxel) prompt cancer cells to self-destruct -- but some tumours stubbornly survive the treatment.
Two studies have now independently pinpointed a gene that lies behind at least part of this resistance. The discovery could help oncologists predict which patients are likely to respond to Taxol and drugs with similar actions, and which may not. It also flags up new targets for cancer therapy.
Taxol belongs to a class of chemotherapy drugs that work by binding to tubulin, a key protein in the network of filaments that maintains a cell's structure. Cells hit with anti-tubulin drugs "try to divide but they can't", says Ingrid Wertz, a molecular biologist at biotechnology company Genentech, headquartered in San Francisco, California.
Cancer cells that respond to Taxol eventually die. But other cells resist the treatment. In 2007, Wertz and her colleagues began asking why. The team found that, in responding cells, levels of one protein in particular, MCL1 - part of a family of proteins already known to affect a cell's life-cycle - were markedly lower immediately after treatment with Taxol (and with another anti-tubulin drug, vincristine). Further experiments showed that a known cancer-fighting protein, FBW7, was destroying MCL1.
Defects in the FBW7 gene had already been linked to a variety of cancers, including breast and colon. Wertz reasoned that its absence might in particular lead to high levels of MCL1, and explain why some cancer cells don't die when treated with anti-tubulin drugs.
Sure enough, the researchers observed that ovary and colon tumour cells with mutations in FBW7 had higher levels of the MCL1 protein and were more resistant to anti-tubulin drugs than cells with working copies of the gene.
Different route, same outcome
Meanwhile, Wenyi Wei, a molecular biologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts, and his colleagues were also studying FBW7's effects. Wei's group was focusing on a particular disease: T-cell acute lymphoblastic leukaemia (T-ALL), in which an estimated 30% of all cases have cells with FBW7 defects. These cells had high levels of other proteins that normally induce cell death, and yet they did not die. Wei's research into why that was led him to the same explanation: without the FBW7 protein, the cells did not break down MCL1, a necessary step for their death. "We went about it in opposite ways but ended up at the same conclusion," Wertz says, "which was really cool."
Wei and his colleagues also found a link to drug resistance. They exposed T-ALL cells to ABT-737, an experimental drug discovered by US healthcare firm Abbott, based in Abbott Park, Illinois (a newer version, ABT-263, is now in phase II clinical trials). This drug does not attack tubulin, but kills by blocking other proteins that promote cell survival. Again, cells with an FBW7 defect, and high levels of MCL1, are less sensitive to the drug. But the researchers found a way to solve this problem: by treating the cells with an agent called sorafenib, which lowered MCL1 levels and restored cells' sensitivity to the experimental drug.
The studies suggest that oncologists may be able to tailor their treatments based on whether or not patients have a defective FBW7 gene in tumour cells. "I think it has potential implications for any cancer in which these anti-microtubule agents are used," Wertz says.
Still, there are other ways to resist Taxol and similar drugs. Cancer cells may contain mutated tubulin, meaning anti-tubulin drugs can't bind to them in the first place. Or they may contain extra protein pumps that enable cells to quickly eliminate chemotherapy drugs. Anthony Letai, an oncologist at the Dana-Farber Cancer Institute in Boston, says that the importance of the MCL1 pathway in conferring drug resistance probably varies depending on the type of cancer.
"As with any study, you don't know how generalizable it is beyond these cell lines that they study," says Letai. "There's probably plenty of cell lines in which these effects are not observable." The trick, he adds, will be to figure out which cancers follow this model.
Hayley McDaid, a cancer biologist at Albert Einstein College of Medicine in New York, suggests looking at archived specimens from cancer patients treated with Taxol-like drugs. If Wertz's model holds, the researchers should find a correlation between the presence of FBW7 and response to Taxol. "We need to go in and actually do some sequence analysis on those specimens," she says.Bruce Clurman, an oncologist and molecular biologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, says the findings are exciting and provocative, but preliminary. He notes that FBW7 targets a number of proteins for destruction, not just MCL1. "When you disrupt FBW7, it's hard to know which of these downstream targets are playing what role in the development of cancer." These studies focus on FBW7's role in regulating MCL1, but "it's certainly far from the whole story", he says.