Researchers find new approach to treat drug-resistant HER2-positive breast cancer

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. Using human cell lines of the HER2-positive breast cancer subtype, researchers from the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center have detailed the surprising ways in which resistance manifests and how to defeat it before it happens.

The discovery, published today in the journal Cell Reports, 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.

This study, a collaboration of 20 University of North Carolina researchers, 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.

"This research was done in cell lines of human HER2-positive breast cancer, not in patients; but the results are very striking," said 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."

The HER2-positive subtype accounts for 15 to 20 percent of all breast cancer diagnoses. Only about one-third of these patients respond well to standard therapy. But even patients that initially respond eventually develop resistance. This is a universal problem of drugs that target specific proteins called kinases that drive tumor growth. Kinases 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.

Tim Stuhlmiller, PhD, a postdoctoral fellow in Johnson's lab and first author of the paper, conducted experiments using a technique to determine kinase activity on a global scale throughout a group of given cells - a technology that Johnson's lab had previously developed.

Stuhlmiller 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. Not just one or two kinases activated to beat the lapatinib. Many kinases responded. And they were not the same kinases from cell line to cell line. But they did the same thing: they ensured that the cancer cells survived and grew.