Combination treatment against resistance to breast cancer therapy

Combination treatment against resistance to breast cancer therapy

9 Apr 2015

Resistance to therapy is a major problem in the cancer field. Even when a treatment initially works, the tumors often find ways around the therapy. Researchers are trying to manage resistance by using human cell lines of the HER2-positive breast cancer subtype. In a new study, they have detailed the surprising ways in which resistance manifests and how to defeat it before it happens.

The discovery provides the experimental evidence for the potential development of a novel combination therapy for HER2-positive breast cancer. The combination includes the FDA approved drug lapatinib and a new experimental drug called a BET bromodomain inhibitor, which works by disrupting the expression of specific genes.

“Our goal: a durable and lasting response to treatment”

This study, a collaboration of 20 researchers of the University of North Carolina, is the first time a BET bromodomain inhibitor has been shown to prevent the onset of resistance to drugs such as lapatinib in breast cancer cells.

"Although, this research was done in cell lines of human HER2-positive breast cancer and not in patients, the results are very striking," confirms Gary Johnson, PhD, Kenan Distinguished Professor and chair of the department of pharmacology, member of the UNC Lineberger Comprehensive Cancer Center, and senior author of the paper. "The combination treatments are currently being tested in different mouse models of breast cancer. Our goal is to create a new kind of therapy that could help oncologists make the response to treatment more durable and lasting for breast cancer patients."

“Each cell line resisted in different ways”

The scientific team was able to see what happened to HER2-positive human cancer cells when treated with the HER2 inhibitor lapatinib. As expected, each cell line developed resistance to the drug. But, surprisingly, each cell line resisted in different ways. Let’s see why.

Specific proteins called kinases that drive tumor growth, are essential for cellular activities, such as movement, division, and signaling to other proteins to promote cell survival and growth. In this subtype of breast cancer, HER2 is the primary kinase involved in the growth of these tumors. When it's blocked with a drug like lapatinib, cancer cells have ways to get around the roadblock by using other kinases.

Annihilated cancer cells with the combination therapy

This research strongly suggests that there are many different ways HER2-positive cancer cells can compensate for the initial blockage of the HER2 protein. Thus, targeting all of these specific kinases would be extremely difficult. "The more drugs you try to use, the more toxic that would be for patients and the lower the dose people would be able to tolerate” commented one of the scientists.

However what the research team did was to use a different kind of drug to block that entire massive kinase response before it ever happened. During experiments, the team found that BET bromodomain inhibitors targeted the gene transcription of most of the kinases responsible for resistance. By combining lapatinib with a BET bromodomain inhibitor, they found that the HER2 kinase was blocked, as planned. Also, the massive kinase activation that typically followed HER2 inhibition never happened. The second drug suppressed the kinase response.

"We blocked it before it could happen," Stuhlmiller said. "In all five cell lines we tested, there were no cancer cells left because the combination therapy blocked their growth. Essentially, we made the activity of lapatinib durable." As a result, the cancer cells were annihilated.

 

Source: Science Daily