Study Offers Solution for HER2 Resistance in Breast Cancer

Ruth Lupu, PhD

By targeting the HER2 protein’s ability to transform cells, therapies such as trastuzumab (Herceptin) and pertuzumab (Perjeta) have significantly extended the survival of women with HER2-positive breast cancer. However, major treatment challenges still remain for this breast cancer subtype, according to Ruth Lupu, PhD, professor of Laboratory Medicine and Pathology at Mayo Clinic.

“These drugs are successful, but the problem is that patients develop resistance after a while when they are treated with trastuzumab,” said Lupu.

Lupu and her Mayo Clinic team are examining a potential solution. They are investigating a novel method that blocks a key region in the extracellular domain (ECD) and inhibits HER2 dimerization and signaling. They hypothesize that HER2 activation occurs through a section of protein that is ultimately responsible for forming pairs with itself or other proteins of the same receptor family. If such a site exists, then blocking it would deactivate HER2, stopping tumor growth and metastasis. This has the potential to effectively circumvent resistance.

Results from their study were recently published in the Journal of the National Cancer Institute. According to the study, removing 16 amino acids (HER2-ECD-Δ451—466) in the ECD domain of HER2 completely disrupted the oncogenic potential of HER2. Unlike wild-type HER2, a mutant protein that was missing this 16 amino acid sequence could not transform normal cells into cancer.

The mutant inhibited anchorage-independent growth (mean number of colonies: mutant, 70, 95% CI, 55-85; wild-type, 400, 95% CI, 320-480; P <.001) and increased sensitivity to treatment in both transformed and non-transformed cells. Overexpression of HER2-ECD-Δ451—466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested.

For comparison, the researchers evaluated the impact of adding the mutant protein to HER2-positive breast cancers versus treating HER2-positive cells with trastuzumab, pertuzumab, and cetuximab. The results showed that the mutant protein stopped the growth of the tumor cells and outperformed all three targeted drugs.

“The study demonstrates that there is a region in the HER2 protein that is involved in partnership or dimerization of the HER2 receptor with other receptors in the HER family,” said Lupu. “We identified a particular region that when it mutates, it prevents not only the homodimerization of the receptors but also the heterodimerization. Therefore, we anticipate that the use of a drug that targets that particular region will be much more useful than any drug that we are currently using in the clinic.”

There are currently no approved treatments that specifically target the ability of HER2 cells to join together or with other proteins, an essential first step in tumor growth. Lupu and her colleagues are now confirming the antitumor activity of this potential HER2 “master switch” in animal models. They will then move on to clinical testing, and the investigation of drugs—such as mimetic agents, targeted antibodies, and small molecules—that could specifically block this site responsible for HER2’s oncogenic potential.

“This drug does not yet exist; it is a promising area of future research,” said Lupu. “We believe that there is definitely hope because this is the first time that anybody has identified any region that blocks homodimerization and heterodimerization, which will simplify the treatment of the cancer. Rather than combining two, three or four drugs together, this will be a one-stop-shop.”

Amplification of HER2 occurs in approximately 30% of breast cancers and is associated with more aggressive disease progression. HER2 is the only HER family receptor without known ligands. In cancer cells, the ligandless HER2 can be activated either by overexpression or by ligand mediated stimulation of another HER receptor, resulting in the formation of receptor homo- or heterodimers for which HER2 is the preferred partner.

Several HER2-directed agents are in clinical use or at advanced stages of development; however, many breast tumors express multiple HER receptors and co-express one or more HER ligands, which negatively impacts the response to current HER2-targeted therapies.

The research conducted by Mayo Clinic, and any subsequent drugs that may result from the investigation, may be applied in more than just HER2-positive breast cancer, said Lupu.

“This could have possibilities not only in breast cancer tumors that have overexpression of the receptor and amplification of the gene, but also in patients whose tumors not only have overexpression of HER2, but also expression of other HER receptors as well,” she said. “It could also be applied to other carcinomas including ovarian cancer, prostate cancer, and gastric cancer.”

Menendez JA, Schroeder B, Peirce SK, et al. Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling [published online April 17, 2015]. J Natl Cancer Inst. doi: 10.1093/JNCI/djv090.