Biomarkers Indicate Non-Response to Breast Cancer Therapy

A rapid method has been developed to identify biomarkers associated with non-responsiveness to cancer drugs in cell culture. The technology was used to identify a mechanism of resistance to Herceptin-based cancer therapy. These biomarkers were found to have predictive value in patients treated with this drug, thus validating the approach.

The technology used relies on the simultaneous inactivation of thousands of genes through a process known as RNA interference in cells that are sensitive to a specific cancer drug. If the inactivation of a specific gene confers resistance to a cancer drug, cells harboring the inactivated gene can continue to grow in the presence of the cancer drug and can be readily identified. In the present study, deregulation of the phosphatidylinositol 3-kinase pathway, which is mutated in up to half of all breast cancer tumors, was identified as a major mechanism of unresponsiveness to Herceptin-based therapies.

The antibody drug Herceptin targets the HER2 protein, which is hyperactive in about one in four breast cancers, and the HER2 protein contributes to aggressive cancer behavior. Striking initial responses are observed in combination with chemotherapy in more than half of treated patients. However, the majority of responding patients eventually develop resistance to Herceptin-based therapies.

Agendia (Amsterdam, The Netherlands) has acquired rights to the discovery of a major drug resistance mechanism in breast cancer, which could potentially lead to a Herceptin sensitivity test. "The availability of biomarkers that predict responses to cancer therapy is instrumental to the rational use of cancer drugs in the clinic. Elucidating the molecular mechanism of drug resistance can be critical to identify patients that fail to respond to therapy and may help design more efficient treatment protocols,” said Prof. Rene Bernards, Agendia's CSO. "Although more work is needed to further validate our findings, the method is generally applicable to find mechanisms of drug resistance and should expedite the development of biomarkers that are associated with therapy non-responsiveness.”

The discovery of the mechanism of resistance to the frequently used breast cancer drug Herceptin by Prof. Rene Bernard's laboratory was published in the October 15, 2007, issue of the journal Cancer Cell.


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