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Sunday, October 17, 2021

UCD researchers hypothesize cause of breast cancer drug resistance in some patients

UC Davis Cancer Center researchers have found a probable explanation for some tumor cells’ resistance to the breast cancer drug trastuzumab, commonly known by its designer name Herceptin.

Herceptin targets the protein HER2, which is a receptor of tyrosine kinase, an enzyme that encourages cancer cell growth.

In a Mar. 1 study published in Cancer Research by David Shattuck, Jamie K. Miller, Kermit L. Carraway III and Colleen Sweeney, initial results conclude that another molecule known as a MET receptor can act similarly to HER2 in some HER2-positive breast cancer patients, thus inhibiting Herceptin’s effectiveness.

Drug companies have revolutionized the way [cancer] is treated by creating molecular therapies. These therapies essentially target specific pathways in a cancer cell, said Shattuck, a UC Davis biochemistry graduate student and co-author of the study.

But what people don’t understand is how cancer cells are able to adapt to these therapies by basically turning on other signaling pathways, he said.

The research focuses on examining cancer cells’ adaptation to treatment with a particular molecular therapy and figuring out what other signaling pathways are coming on, he said.

The goal is then to treat both of the targets at the same time to provide a better inhibition of cancer cell growth, Shattuck said.

In patients that have a lot of HER2 protein, HER2 drives the growth of breast tumor cells, said Sweeney, associate professor of biochemistry and molecular medicine and co-author of the study.

Herceptin shuts down the HER2 so that the tumor cells can’t grow anymore. In the patients that it does work, it prolongs their survival and it decreases their risk of relapse,where tumor comes back, she said.

It’s a very effective drug, Sweeney said.

However, some tumor cells are inherently resistant to the drug, or develop a resistance over time.

We’re interested in figuring out why, Sweeney said.

Sweeney said the researchers examined some patient specimens and found that some patients that expressed HER2 also expressed significant amounts of the MET receptor.

After conducting experiments in cultured human breast cancer cells, the researchers found that when the MET receptor was inhibited, the cells responded better to Herceptin.

The MET receptor is very similar to HER2, Shattuck said. [It is a] receptor of tyrosine kinase and sits at the membrane of cells.

[The MET receptor] has very similar properties in terms of cell signaling, he said.

It’s very easy for the MET receptor to take over HER2’s job, because it plays a similar role, he said.

When some patients are given Herceptin to target HER2, the tumor cells shift their dependence and use the MET receptor to grow instead, Shattuck said.

What we showed in our paper is that treating a cancer cell with Herceptin and a MET inhibitor can synergistically enhance their effect, he said.

The next step of the research is to further test the combination of Herceptin and MET inhibitors in animal models, and then begin clinical trials to start helping patients, Shattuck said.

Sweeney said this study and studies conducted by other researchers are focusing on ways to individualize cancer treatment.

Researchers are beginning to look at the question How can we personalize therapy so that it’s appropriate for an individual patient? she said.

South San Francisco-based biotechnology corporation Genentech started developing Herceptin in the late 1980s.

Herceptin is Genentech’s wonderdrug, Shattuck said.

The drug, designed to specifically target the HER2 gene, was approved by the Food and Drug Administration in 1998.

There was no successful treatment for HER2-positive breast cancer before Herceptin, said Kimberly Ocampo of Genentech’s corporate relations department.

Before Herceptin, doctors had to treat [HER2-positive breast cancer] with usual methods such as surgery, and radiation therapy, she said.

[Herceptin] is the first HER2 targeted therapy. It really changed the outlook for women who had this type of disease.… The prognosis [for this disease] has become better, she said.

Breast cancer is the most common cancer among American women, except for skin cancers, said an information specialist with the American Cancer Society. The chances of developing invasive breast cancer at sometime in a women’s life is about one in eight or a 12 percent chance.

At this time there are about 2.5 million breast cancer survivors in the United States, he said.

 

ANNA OPALKA can be reached at campus@californiaaggie.com.

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