Powerful predictor of resistance may change management of therapy for breast cancer

Scientists have identified a new mechanism of action for the anticancer drug Herceptin (trastuzumab) that can be used to accurately predict whether or not a breast cancer patient will be resistant to treatment. The finding has dual significance, as it will allow patients who are unlikely to respond to trastuzumab to avoid unnecessary costs and side effects associated with treatment, and it provides new directions for designing strategies for overcoming treatment resistance. The research is published in the August issue of Cancer Cell.

A little less than one-third of human breast cancers are associated with an abundance of a protein called ErbB2. Unfortunately, these patients have a very poor prognosis for survival. Trastuzumab is a carefully designed antibody therapeutic that specifically targets ErbB2 and has excellent therapeutic success, but only for a small percentage of ErbB2-associated breast cancer patients. In addition, some patients suffer severe side effects from treatment. It is not clear what determines a successful response to trastuzumab.

Dr. Dihua Yu from The University of Texas M. D. Anderson Cancer Center in Houston and colleagues looked for a relationship between PTEN and ErbB2 signaling because PTEN, an important tumor suppressor, is present at decreased levels in about half of all breast cancer cells. The researchers found that trastuzumab rapidly activates PTEN in breast cancer cells. Experimental reduction of PTEN in breast cancer cells resulted in trastuzumab resistance. Further, patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab when compared with patients with normal levels of PTEN. Importantly, inactivation of the enzyme PI3K, which antagonizes PTEN, rescued PTEN-deficient breast cancer cells from trastuzumab resistance.

The researchers conclude that the antitumor activity of trastuzumab involves PTEN activation and that PTEN deficiency is an indicator for trastuzumab resistance. This newly identified mechanism of trastuzumab function clearly indicates that responsiveness to the drug depends not only on reduction of ErbB2 but also on the status of PTEN. The finding that PTEN deficiency confers trastuzumab resistance in ErbB2-overexpressing breast cancers is likely to directly impact the clinical management of patients with PTEN-deficient tumors. Further, members of the PI3K pathway, as well as PTEN, are excellent molecular targets for future development of agents for overcoming trastuzumab resistance and for design of novel targeted cancer therapies.

Yoichi Nagata, Keng-Hsueh Lan, Xiaoyan Zhou, Ming Tan, Francisco J. Esteva, Aysegul A. Sahin, Kristine S. Klos, Ping Li, Brett P. Monia, Nina T. Nguyen, Gabriel N. Hortobagyi, Mien-Chie Hung, and Dihua Yu: "PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients"

Publishing in Cancer Cell, August 2004, Volume 6, Issue 2, pages 117-127.

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