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Combination overcomes breast cancer resistance to herceptin
Date:3/13/2011

with Herceptin, it's beautiful."

Another SRC inhibitor, dasatinib, has been approved by the U.S. Food and Drug Administration as an anti-cancer drug, but it has harsher side effects, said Siyuan Zhang, Ph.D., a postdoctoral fellow in Yu's lab and the paper's first author.

A tumor-suppressor's job

In 2004, Yu's lab discovered that loss of the tumor-suppressing gene known as PTEN led to Herceptin-resistant tumors. PTEN is a phosphotase - a protein whose function is to strip phosphate chemical groups off of other molecules.

PTEN has two components, one to remove phosphate groups from lipids, and another to remove them from proteins. PTEN's target protein however, was unknown.

Zhang discovered that SRC is a PTEN target. With its phosphate groups, SRC is active. PTEN stifles SRC by peeling away the phosphates.

If PTEN loss leads to Herceptin resistance, and PTEN targets SRC, would that make SRC the culprit?

On the trail of SRC

In a series of experiments the researchers found:

  • SRC is active in breast cancer cells once vulnerable but now resistant to Herceptin and in cells that are resistant from the start.
  • Activation of SRC drives resistance to Herceptin. Tumors with low SRC levels treated by Herceptin shrunk to 20 percent of their original volume in 21 days while SRC-heavy tumors increased by nearly 400 percent over the same time in mouse experiments.
  • SRC activity correlates with patient response to Herceptin. Assessing SRC activation in samples of 57 human breast cancer tumors, the team found that more than 90 percent of tumors with low SRC responded compared with 40 percent of tumors with active SRC.
  • Patients with little active SRC had a median survival of 57.9 months compared with 34.2 months in those with high SRC activity.
  • SRC is activated by a number of receptor tyrosine kinases that cause resistance, including IGF-1R, EGFR, ERBB2, HER3, and Met, separate
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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