BET Bromodomain Inhibitors May Prevent Treatment Resistance in HER2-Positive Breast Cancer

Gary Johnson, PhD

BET bromodomain inhibitors could offer a potential solution to lapatinib resistance in patients with HER2-postive breast cancer, according to a recent article published in CELL Reports.

Using human cell lines of HER2-positive breast cancer, researchers at the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center tested several BET bromodomain inhibitors, including one currently in clinical trials for certain types of leukemia.

The researchers found that BET bromodomain inhibitors targeted the gene transcription of most of the kinases responsible for resistance in HER2-positive breast cancer. By combining lapatinib with a BET bromodomain inhibitor, the HER2 kinase was blocked. Moreover, with the additional drug, the kinase activation that typically follows HER2 inhibition did not occur. The resulting effect of the additional agent was that it enhanced the durability of lapatinib.

For additional insight on these findings, OncLive spoke with senior study author Gary L. Johnson, PhD, Kenan Distinguished Professor and chair of University of North Carolina School of Medicine’s Department of Pharmacology and member of the UNC Lineberger Comprehensive Cancer Center.

OncLive: What makes this research significant?

Dr Johnson: What my laboratory works on, which is mostly in breast cancer, is adaptive bypass pathways that occur when you use a kinase inhibitor, such as lapatinib or other targeted kinase inhibitors. I have developed methods where I can measure the activation status of the kinome as a whole, not just as a kinase pathway. We have shown that the kinome is much more resilient than we thought it would be to targeted kinase inhibition.

Many of these drugs initially have really strong biologic effects, but resistance invariably develops. Some of the kinase inhibitors generally don’t have really strong, durable responses because of these adaptive bypass pathways where the tumor cell recognizes this inhibition. The tumor cell is actually able to circumvent the inhibition and restimulate growth and create drug resistance. We showed that this is due to reactivation of more than one kinase and these adaptive bypass pathways.

Most oncologists are looking for combination therapies they could use to solve these issues, but what we’ve shown is there is a significant heterogeneity of this response. We took a different approach. Rather than trying to find a second inhibitor, which the tumor cell is also going to find a bypass mechanism for, we tried to block the initial transcriptional response. This involves the regulation of several different transcriptional kinases. If we can block that initial regulation of these kinases, we could block the onset of the adaptive bypass pathways and make single-agent drugs, such as lapatinib, durable. That is what we did.

This is the first example of using an epigenetic modifying enzyme inhibitor and actually blocking the adaptive bypass response. We can also show that HER2-positive cells that are resistant to lapatinib can become sensitive again to the agent by using BET bromodomain inhibitors.

Can you expand on what BET bromodomain inhibitors are and how they work?

There are four BET proteins; three of them are expressed in most tumor cells. They have a protein domain called a bromodomain. Approximately 75 proteins have bromodomain, and each subset has a unique bromodomain. There are inhibitors that specifically block the BET sub-family protein bromodomain, and these bromodomain are called acetyl readers. The histones in the chromatin are modified by acetylation. When they become acetylated, they recruit bromodomain family proteins by the binding of the bromodomain from the BET protein to these acetylated histones. These are involved in recruitment of transcription factors and driving the transcriptional response. We showed that these BET bromodomain proteins are critical for the adaptive bypass response for the upregulation of specific receptor tyrosine kinases. By blocking that transcriptional response, we are able to enhance the efficacy of lapatinib and growth inhibition.

What are oncologists currently doing to overcome lapatinib resistance in HER2-positive breast cancer?

They don’t currently have a mechanism to prevent the adaptive bypass. Oncologists are trying to respond to the adaptive bypass after it happens. They are trying to find a second kinase inhibitor, or a second inhibitor, that will work in combination with the first drug.

This adaptive bypass response is a major problem in the clinic. The heterogeneity of the response is significant enough that you have to do it on a patient-by-patient basis. However, these adaptive responses tend to be reversible, so one of the things that oncologists are trying to do is treat for a certain period of time, take the drug away for a couple of weeks, and then put the patient back on the drug. They are doing this is in immunotherapy, where they use an antibody for a certain amount of time, take the patient off the antibody, put them on kinase inhibitors for a certain period of time, and then repeat that kind of scheduling. They are just working those out.

What are the next steps for your research?

We have done animal data, but it is not published yet. BET bromodomain inhibitors are such new agents and further research is needed on them, so we can’t actually do a combination trial in a patient yet. However, there are cell line and mouse studies that confirm what we are doing.

Our next step with HER2-positive breast cancer is to finish several different animal models. We’ve also gone further in understanding the molecular biology of the mechanism of action. What we’d like to be able to do In the near future, we would like to do a window trial, which is a short-term trial created for information gathering. The patients in the trial have been diagnosed with HER2-positive breast cancer and receive lapatinib either with or without a BET bromodomain inhibitor. The goal is to get the same response in patients as we did in cells and mice. However, BET bromodomain inhibitors are still in phase I trials, so we need more data on that drug first.

Could this BET bromodomain inhibitor theoretically work with other drugs, or within other cancers to prevent resistance?

We have data that shows there is a similar kind of response in triple-negative breast cancer using different but similar drugs, including trebananib. That is a very active area of research in my laboratory. We have a lot of animal data and a lot of cell line data, but we actually have data in triple-negative breast cancer in patients that these adaptive bypass pathways are activated within one week of drug treatment. This is a major problem. Within days of treatment, the tumor is already responding to try and develop mechanisms of resistance to the drug. We think this research may be applicable to many different cancer types. It may be a paradigm shift in the way we can target and block the adaptive mechanisms of tumor cells.