BioWorld International Correspondent

LONDON - A new understanding of the mechanism by which breast cancers become resistant to the commonly used drug tamoxifen could help clinicians direct the drug to those women most likely to benefit from it.

The discovery, which made use of a new approach that could provide clues to many more drug targets, brings closer the time when physicians will be able to tailor therapies according to the molecular characteristics of tumors.

Alan Ashworth, professor of molecular biology at the Breakthrough Breast Cancer Research Centre, at the Institute of Cancer Research in London, UK, told BioWorld International: "The whole philosophy behind this work is that the levels of expression of individual genes can indicate who will respond to which treatment. If we can identify those people who will not benefit from a certain drug, we can then offer them something else which might help them more."

Ashworth, together with co-author Christopher Lord, also at the Institute of Cancer Research, and colleagues report their findings in a paper in the Feb. 4 issue of Cancer Cell titled: "Identification of CDK10 as an Important Determinant of Resistance to Endocrine Therapy for Breast Cancer."

The team has focused for several years on understanding the molecular mechanisms that determine whether a tumor is sensitive to a cancer drug or resistant to it. They chose to study resistance to tamoxifen. Although the drug is highly effective in many women with oestrogen-receptor-positive breast cancer, all patients with metastases and 40 percent of those with early stage breast cancer eventually relapse with tumors that are resistant to it.

To try to explore the reasons for the development of resistance to tamoxifen, Ashworth, Lord and their colleagues used RNA interference to silence all the genes in the genome that they thought could possibly be involved in conferring resistance. These genes included all of those involved in signal transduction - in other words, all of those encoding kinases.

The availability of libraries of interfering RNAs, each one of which can silence a single specified gene, meant that the researchers were able to screen the entire genome for kinases that, when absent, would cause tumor cells in culture to become resistant to tamoxifen.

Their search paid off. As reported in Cancer Cell, they discovered that absence of a gene called CDK10 had that undesirable effect.

"Very little is known about CDK10," Ashworth said, "and it has not been implicated in tamoxifen resistance before."

Further experiments allowed them to show how the gene regulates resistance to tamoxifen. They were able to show that when expression of CDK10 is inhibited, a pathway involving another kinase, MAP kinase, is upregulated.

They also were able to demonstrate that the tumors of women who had not done well on tamoxifen tended to have low levels of expression of CDK10.

Additional studies showed that methylation of the CDK10 gene also correlated with resistance. It is well established that methylation of genes is a way by which the cell can control their expression. That observation suggested a mechanism that could switch off CDK10 expression in tumor cells.

"Putting together the cell biology, with the observation that tumors that are resistant to tamoxifen tend to have low levels of CDK10," Ashworth said. "This starts to provide a persuasive argument that this gene plays an important role in the mechanisms of resistance to tamoxifen in human breast cancer."

He predicted that it will be possible to use measurements of CDK10 levels as an indicator of who will do well on tamoxifen, and who may do less well, and should be offered alternative treatments. The team is currently actively pursuing that approach.

In addition, women whose tumors have low levels of CDK10 also have high levels of MAP kinase. They may benefit from a new generation of drugs called MAP kinase inhibitors, which currently are under development as a treatment for cancer, Ashworth added.

Could CDK10 have a role in resistance to other anticancer drugs used to treat other types of cancer? "We have not looked at that yet, but it seems logical that it might," Ashworth concluded.