Mayo Clinic study uncovers mechanism behind resistance to HER2 breast cancer drug

UAE— Mayo Clinic researchers have identified a mechanism that may explain why some HER2-positive (HER2+) breast cancers fail to respond to trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) that has improved outcomes for many patients with advanced disease.

The study, published in Nature Cancer, found that a shortened form of the HER2 protein, known as p95HER2, can alter how cancer cells respond to T-DXd.

The researchers say the finding could help guide the development of more targeted treatment combinations for patients whose tumors produce the protein.

Shortened HER2 protein linked to resistance

ADCs combine a cancer-targeting antibody with a potent chemotherapy drug to deliver treatment directly to tumor cells.

However, although T-DXd has demonstrated significant benefits in HER2+ breast cancer, some patients eventually fail to respond to the treatment.

Researchers in Mayo Clinic’s Oncoimmune Signaling and Therapeutics Laboratory investigated the biological mechanisms that could contribute to this resistance.

They found that p95HER2, which occurs in a subset of HER2+ breast cancers, behaves differently from the full-length HER2 protein.

According to the researchers, p95HER2 triggers distinct cellular signals that can create an immune-protected environment around cancer cells.

This signaling may allow tumor cells to withstand the effects of T-DXd.

“While T-DXd has shown remarkable results for many patients, it hasn’t worked for everyone with advanced HER2+ breast cancer,” said Peter Lucas, M.D., Ph.D., vice chair for research in the Department of Laboratory Medicine and Pathology at Mayo Clinic and co-senior author of the study.

The findings suggest that p95HER2 does more than simply indicate the presence of HER2 in a tumor.

Instead, the protein may actively contribute to treatment resistance by changing the tumor’s biological environment.

Neratinib targets p95HER2

The researchers also examined whether existing medicines could interfere with p95HER2 activity. Their experiments identified neratinib as a potentially effective option.

In preclinical models, neratinib blocked p95HER2 signaling and led to complete degradation of the shortened protein in cancer cells.

“Treatment with neratinib results in complete p95HER2 degradation, abolishing the protein from the cancer cells in our preclinical models,” said Dong Hu, Ph.D., a research scientist in Laboratory Medicine and Pathology at Mayo Clinic and lead author.

Based on the findings, the researchers are considering a clinical trial combining neratinib with T-DXd in patients with HER2+ early breast cancer.

The proposed study would assess whether the combination can improve treatment responses in tumors that produce both p95HER2 and the full-length HER2 protein.

The research team emphasized that this combination represents one of several potential treatment strategies for HER2+ breast cancer.

“No single, one-size-fits-all approach to treatment will work for every patient with HER2+ breast cancer,” said Linda McAllister, M.D., Ph.D., a pediatric hematologist/oncologist at Mayo Clinic and co-senior author.

The researchers said understanding how p95HER2 influences treatment response could support the development of customized therapeutic approaches for patients whose tumors express the shortened protein.