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Hit multiple targets for maximum benefit in HER2-positive breast cancer, studies suggest
Date:3/8/2011

Combining targeted therapies might be required for maximum anti-tumor activity when treating HER2-positive breast cancers, according to two new studies by Vanderbilt-Ingram Cancer Center (VICC) investigators.

The findings, reported in two papers in the Proceedings of the National Academy of Sciences (PNAS), suggest that upregulation of the HER3 receptor limits the effectiveness of two classes of targeted therapies (HER2- and PI3 kinase-targeted therapies). Therefore targeting HER3 together with these agents should improve their clinical utility.

Around 25 percent of breast cancers have increased expression of the HER2 receptor, which is associated with more aggressive tumors and a poorer prognosis. HER2-targeted therapies like trastuzumab (Herceptin) and lapatinib (Tykerb) are effective in many women with HER2-positive breast tumors.

"But even in patients who respond to HER2-targeted therapies, the clinical response tends to be short-lived and tumors become resistant," said Carlos Arteaga, M.D., professor of Medicine and Cancer Biology, and director of the VICC Breast Cancer Research Program.

HER2 is a member of the EGF receptor family involved in signaling pathways that promote cell growth. HER2 must interact and form complexes with other members of the EGF receptor family, and its main partner in activating pathways that promote tumor growth is HER3. This complex of HER2/HER3 is a potent activator of the PI3K/Akt pathway, the key survival pathway in HER2-positive cancers.

"Based on this evidence, we hypothesized that, for these therapies to have maximum effect, HER3 and its output to the PI3K/Akt pathway must be completely shut down," Arteaga said.

A postdoctoral fellow in Arteaga's laboratory, Joan Garrett, Ph.D., led experiments to examine the effect of the HER2 tyrosine kinase inhibitor, lapatinib, on HER3 expression and activity.

She found that inhibiting HER2 with lapatinib led to an increase in HER3
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Contact: Melissa Marino
melissa.marino@vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert

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