Dennis Slamon, MD, PhD
Director, Clinical/Translational Research Director, Revlon/UCLA Women’s Cancer Research Program Chief, Division of Hematology/Oncology Jonsson Comprehensive Cancer Center University of California, Los Angeles
Carlos L. Arteaga, MD
Director, Breast Cancer Research Program Associate Director, Clinical Research Professor of Medicine and Cancer Biology Vanderbilt-Ingram Cancer Center Nashville, TN
Dennis Slamon, MD, PhD, played a leading role in the research that resulted in the development of Herceptin in the 1990s and remains involved in research into targeted therapies. Carlos L. Arteaga, MD, focuses on the role of signaling by oncogenes in the progression of breast tumor cells and molecular therapies in breast cancer. They discussed recent advances in separate interviews with OncologyLive
What role does HER2 play in normal cells and in the development of cancer?
In normal cells, human epidermal growth factor receptor 2 [HER2] is a critical member of the HER receptor family that is involved in proliferation, differentiation, motility, and programmed cell death, all critical functions for normal cells. In malignancy, the gene is altered by amplification in about 20% to 25% of human breast cancers and a smaller percentage of other human cancers. When amplified, the expression of HER2 goes way beyond its normal dynamic range—there is a wide range of normal HER2 expression—so that you get pathologic overexpression. When overexpressed to this extent, it plays a dominant role in proliferation and motility and resistance to hormonal control.
How important is HER2 dimerization in the development of cancer?
Clearly, homodimerization and heterodimerization are the most effective forms of signaling that the HER family executes, and when the gene is amplified in cancer it is probably still working through dimerization partners, so it plays an important role.Arteaga:
HER2 dimerization (both ligand-dependent and ligand-independent), particularly HER2-HER3 dimer formation, is the main mechanism of signaling through HER2. HER2-HER3 dimerization is a particularly important aspect of HER2 signaling as these dimers potently signal to the phosphatidylinositol-3-kinase (PI3K) survival pathway and are the main mechanism driving HER2-positive cancers.
What are HER2 dimerization inhibitors, and how important is this therapeutic class?
All of the antibodies directed against the HER2 extracellular domain (ED) play a potential role in inhibiting dimerization. The two that are currently out there are the approved drug trastuzumab and the experimental drug pertuzumab, which bind to different regions on the ED. Each of them plays a role in inhibiting the dimerization phenomena.
As single agents, the most effective is trastuzumab. When we compared trastuzumab activity preclinically, we looked at all the drugs, including pertuzumab (which used to be called 2C4 when I worked on it), and the best antibody for inhibiting HER2 growth in vivo and in vitro was the drug that became trastuzumab, and pertuzumab was maybe the second or third best.
But when you hit the receptor twice, it appears you have even better activity. We had preclinical data from our lab from several years ago that demonstrated this, and we also had data that showed that lapatinib plus trastuzumab was also better than either agent alone. So, it appears that two assaults on the receptor gives you synergistic activity.Arteaga:
These are drugs or molecules that disrupt the association or coupling of HER2 to other receptors such as epidermal growth factor receptor (EGFR) and HER3. These would include trastuzumab, pertuzumab, and HER3 antibodies.
Overall, these represent an important class of agents as they disrupt a central mechanism of signaling by the HER2 receptor. In addition to trastuzumab and pertuzumab, there are two HER3 antibodies in clinical development that disrupt heregulin (HER3 ligand)-induced HER2-HER3 dimerization: MM-121 from Merrimack and U3-1287 from U3 Pharma and Daiichi-Sankyo.