What Tumors Can Do to Resist Chemotherapy

Taxol (paclitaxel), a powerful chemotherapy drug, causes cancer cells to self-destruct. However, some tumors continue to survive.

Two studies have now independently pinpointed a gene that lies behind at least part of this resistance. This discovery may help oncologists to predict the likelihood of patients responding to Taxol or drugs that have similar effects. The discovery could also help oncologists identify new potential targets for treatment of cancer.

Taxol is one of a group of chemotherapy drugs which works by binding to tubulin. Tubulin is a crucial protein that helps maintain a cell’s structure. Anti-tubulin drugs cause cells to "try and divide, but they don't," says Ingrid Wertz (molecular biologist, biotech company Genentech, San Francisco).

Taxol is a treatment that kills cancer cells. Some cells are resistant to the treatment. Wertz began to investigate the reason in 2007 with her coworkers. In responding cells, the levels of MCL1, a protein that is part of an already-known family of proteins, were lower after Taxol treatment (and also with vincristine, which are anti-tubulin drugs). Further tests revealed that MCL1 had been destroyed by FBW7 - a cancer-fighting protein.

Several types of cancers have been associated with defects in the FBW7 genes, including colon and breast. Wertz suggested that it might be missing in some cases, leading to high levels MCL1, which could help explain why cancer cells can survive when given anti-tubulin drugs.

The researchers found out that colon and ovary cancer cells with mutations at FBW7 had higher MCL1 levels and more resistance to anti-tubulin drugs, than cells with functional copies.

The same result, different route

Meanwhile, Wenyi Wei, a molecular biologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts, and his colleagues were also studying FBW7's effects. The focus of Wei's research was on T-cell acute lymphoblasticleukaemia (T–ALL), which is where 30% of all cases contain cells that have FBW7 deficiencies. The cells were high in other proteins, which normally cause cell death. Yet they didn't die. Wei spent his time researching why this was so and came up with the same conclusion: cells that did not have the FBW7 proteins could not degrade MCL1, a critical step to their death. Wertz says that while we tried to reach different conclusions, it led us all to the same result.

Wei and his collaborators also discovered a link between drug resistance. T-ALL cells were exposed by Wei and his colleagues to ABT737. This experimental drug was developed by Abbott in Abbott Park (IL). ABT-263, a more recent version of the drug, is currently being tested in clinical trials. Although this drug does not target tubulin, it kills cells by blocking the activity of other proteins which promote cell survival. The drug is less effective in cells that have FBW7 or high levels of MCL1. The researchers discovered a solution: they treated the cells with sorafenib. It decreased MCL1 levels in the cells and increased their sensitivity to the 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. Wertz believes it could have potential consequences for all cancers in which anti-microtubule agent are used.

However, Taxol can be resisted in other ways. Mutated tubulin in cancer cells could mean that anti-tubulin medications won't be able to attach to them. Extra protein pumps may be present in cancer cells that allow them to eliminate chemotherapy drugs quickly. Anthony Letai (an oncologist at Dana-Farber Cancer Institute) in Boston says that depending on the cancer, the MCL1 pathway is important in conferring drug resistant.

Letai states, "As with all studies, it's impossible to know how generalizable beyond the cells they are studying." These effects may not be visible in many cell lines, however. He says that the trick is to determine which types of cancer follow this pattern.

Hayley McDaid from Albert Einstein College of Medicine, New York suggests studying archived samples of patients with cancer treated using Taxol-like medicines. If Wertz is right, researchers will need to find a link between the response of Taxol and the presence or absence of FBW7. The findings of the Fred Hutchinson Cancer Research Center's Bruce Clurman (an oncologist, molecular biologist, and oncologist) are both exciting and provocative. However, the research is still preliminary. He noted that FBW7 does not target MCL1 alone, but targets a wide range of proteins. It's difficult to determine which downstream targets play what roles in cancer development when FBW7 is disrupted. These studies focus on FBW7's role in regulating MCL1, but "it's certainly far from the whole story", he says.