Accounting for 15–20 % of breast cancer cases, the HER2-positive subtype is known for its ability to develop resistance to standard cancer therapies. A team based at the University Of North Carolina School Of Medicine and Lineberger Comprehensive Cancer Center (NC, USA) have recently proposed that a novel combination of lapatinib and an experimental BET bromodomain inhibitor could overcome multiple HER2 mechanisms of resistance and kill cancer cells. Their findings were published recently in Cell Reports.
“This research was done in cell lines of human HER2-positive breast cancer, not in patients; but the results are very striking,” commented Gary Johnson, a member of the 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.”
Utilizing HER2-positive breast cancer cell lines, the team employed a technique that allowed them to monitor global kinase activity. This method allowed them to determine the events unfolding when the cells were treated with the HER2 inhibitor lapatinib. Each cell line examined was seen to develop resistance to the kinase inhibitor and the investigations revealed that this resistance was the result of the activation of many different kinases, which allowed the cancer to continue to grow.
“It was amazing,” reported first author Tim Stuhlmiller (Lineberger Comprehensive Cancer Center). “We found this massive upregulation of many different kinases that could either reactivate the main HER2 signaling pathway or bypass it entirely. In fact, we discovered that nearly 20% of the cell’s entire gene expression profile was dysregulated when we treated the cells with lapatinib.”
Stuhlmiller continued, explaining the problems associated with targeting all the various kinases upregulated to bring about therapy resistance: “Because of toxicity concerns, you couldn’t inhibit all these kinases that potentially help cancer cells compensate in the face of a HER2 inhibitor. 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.”
These findings led them on to investigating BET bromodomain inhibitors – agents that target proteins involved in gene transcription. They tested several of these and were able to establish that BET bromodomain inhibitors target gene transcription of most of the kinases responsible for resistance. Combining lapatinib with a BET bromodomain inhibitor in breast cancer cell lines, the team established that HER2 was blocked and the subsequent upregulation of other protein kinases did not occur.
“We blocked it before it could happen,” Stuhlmiller continued. “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.”
This study marks the first instance of a BET bromodomain inhibitor showing an ability to prevent the onset of resistance to drugs such as lapatinib in breast cancer cells. Johnson, Stuhlmiller and colleagues are now working on reproducing these results in animal models, and further investigating the impact of BET bromodomain inhibitors in other breast cancer subtypes.