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.