HER2-Positive Breast Cancer: Molecular Mechanisms of a Novel Small Molecule Inhibitor
Abstract
HER2+ breast cancer remains a grave clinical problem and a serious scientific challenge. Today s treatment options are very limited. We have discovered the potent cell killing activity of a Food and Drug Administration (FDA)-approved drug, ibrutinib, marketed as Imbruvica, specifically against HER2+ breast cancer cells. Ibrutinib is not significantly active against other types of breast cancer cells. Because ibrutinib is FDA-approved, it could rapidly advance to become an important treatment option in HER2+ breast cancer. In this application, we propose two specific aims: (1) find the specific ibrutinib drug targets in HER2+ breast cancer cells and (2) test for the ability of ibrutinib to overcome resistance to treatment. This work will lay the scientific foundation for the use of ibrutinib in breast cancer. Because ibrutinib shows high specificity for HER2+ breast cancer, there must be specific drug targets in these cells that are not present or not important in other breast cancers. Ibrutinib functions by inhibiting the activity of proteins called kinases, and unlike other kinase inhibitors, once it binds to its target, it cannot come off. It is an irreversible killer of kinases. HER2 is such a kinase that can be inhibited by ibrutinib, but there are many other related cellular proteins that could be responsible for the high sensitivity of HER2+ breast cancer cells to ibrutinib. In order to identify these targets, we will tag the ibrutinib drug. The tagged drug will enter cells and combine with its targets. The cells are then broken open, and the drug, now bound to target proteins, is pulled out from the mixture of all the other cellular components. This is possible because the tag binds to chemically modified beads that are added to the mixture, and these beads can be easily separated from the rest of the components. It is as if we had placed a small piece of iron on the drug, let it find its targets, and then pull the drug and targets out from the cellular soup with a magnet. Once the targets are recovered in this way, they can be identified by mass spectrometry, a standard tool in the study of proteins. We will obtain a list of these targets that ibrutinib sees in HER2+ breast cancer cells, but not in HER2- breast cancer cells. We can then investigate the activities of these targets and the effects of ibrutinib on these activities. We will learn which targets have to be inhibited to kill HER2+ breast cancer cells. This knowledge will also enable us to look for other drugs that work against such critical targets. HER2+ breast cancer usually becomes resistant to treatment, often by a change in HER2 that blocks drug binding. We have analyzed the structure of such a drug-resistant HER2 molecule and found that ibrutinib, in contrast to other drugs, will still be able to bind effectively. We therefore expect that ibrutinib can overcome this type of drug resistance in HER2+ breast cancer and plan to examine this possibility. The work proposed here could propel ibrutinib to first line treatment in HER2+ breast cancer. Ibrutinib could transform management of HER2+ breast cancer. It is an approved, orally available drug. Its side effects are modest. Its potency against HER2+ breast cancer rivals the best cancer drugs available. We need to know how it works, and we should explore its potential to break drug resistance in HER2+ breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510033
Entities
People
- Peter K. Vogt
Organizations
- Scripps Research
- United States Army