Tumor cells in a particular subset of breast cancer patients churn out too much of a protein called ErbB2—also often called HER2—which drives the cells to proliferate unchecked. Patients unlucky enough to be in this group—about one in four—have poorer prognoses and clinical outcomes than those who don’t.
The drugs Herceptin and Lapatinib, prescribed in combination with other chemotherapeutic agents, have improved this picture significantly, but leave plenty of room for improvement: they suppress ErbB2 but are effective against less than half of ErbB2-producing tumors. Moreover, patients with tumors that do respond usually develop resistance to these drugs.
A team of scientists at Cold Spring Harbor Laboratory has just published research identifying an enzyme called Brk that may serve as a target for future drugs developed to fight ErbB2-positive tumors. Brk, they report, helps these tumors become virulent and is also implicated in the process through which the tumors develop drug resistance.
“The limited success of existing therapy suggested to us that factors besides ErbB2, or proteins that collude with ErbB2, might nullify the effects of Herceptin and Lapatinib,” explained CSHL Professor Senthil Muthuswamy, Ph.D., leader of the research team and corresponding author of the paper, published online August 21 ahead of print in Proceedings of the National Academy of Sciences.
In the hunt for ErbB2’s co-conspirators, Dr. Muthuswamy’s team focused on Brk, which they knew to be over-produced in many other types of cancer, including two-thirds of all breast cancers. A detailed analysis of changes that occurred in the genomes of a sample of breast cancer patients helped the group confirm that the expression of ErbB2 and Brk was directly linked.
By forcing the production of both ErbB2 and Brk within the same cell, they determined how Brk enhances ErbB2 activity and fortifies tumor cells against ErbB2-targeting drugs. “Our results might explain why the strategy of using ErbB2 inhibitors alone to treat breast cancers has fallen short,” noted Dr. Muthuswamy. “These findings may also suggest a way to treat patients with advanced ErbB2-positive tumors and those who’ve developed resistance to ErbB2 inhibitors – an idea that we’re eager to test.”
Release date August 25, 2008
Source: Cold Spring Harbor Laboratory
Filed Under: Drug Discovery