Mayo Clinic researchers have discovered a key reason why certain breast cancers might not respond to an important new class of therapeutics called antibody drug conjugates ADCs. These treatments pair an antibody that targets cancer cells with a strong chemotherapy drug. For many patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancers, ADCs such as trastuzumab deruxtecan T-DXd have dramatically improved outcomes.
The study is published in Nature Cancer.
“While T-DXd has shown remarkable results for many patients, it hasn’t worked for everyone with advanced HER2+ breast cancer,” says co-senior author Peter Lucas, M.D., Ph.D., vice chair for research in the Department of Laboratory Medicine and Pathology at Mayo Clinic. “This indicates that some tumors have built-in resistant mechanisms that prevent the drug from doing its job.”
In the study, researchers in the Oncoimmune Signaling and Therapeutics Laboratory at Mayo Clinic discovered that a shortened version of the HER2 protein, called p95HER2, that is produced by a subset of HER2+ breast cancers can alter treatment response. The protein p95HER2 “signals differently” from the full HER2 oncoprotein — which proved to be the key to how it drives therapy resistance.
“Our discovery that p95HER2 has the unique ability to induce signals that produce an immune-protected microenvironment strongly suggested that p95HER2 could function within cancer cells to actively resist T-DXd,” Dr. Lucas says.
The study also revealed that a drug called neratinib is highly effective at blocking the action of p95HER2, even causing the protein to be degraded.
“In fact, treatment with neratinib results in complete p95HER2 degradation, abolishing the protein from the cancer cells in our preclinical models,” says lead author Dong Hu, Ph.D., a research scientist in Laboratory Medicine and Pathology at Mayo Clinic.
Based on these findings, the research team believes the next step is a clinical trial to evaluate the combination of neratinib with T-DXd in patients with HER2+ early breast cancer. The goal is to determine if this combination therapy can improve the response in cancers that co-express p95HER2 along with full HER2.
They note that this is just one of many therapeutic combinations being considered.
“No single, one-size-fits-all approach to treatment will work for every patient with HER2+ breast cancer,” says Linda McAllister, M.D., Ph.D., a pediatric hematologist/oncologist at Mayo Clinic and co-senior author of the study.
However, with the discovery of p95HER2’s role, a clear roadmap for future treatment is in sight.
“Having this new understanding of why T-DXd does not always work helps us to envision next steps toward customized therapies and more cures,” Dr. Lucas says. “It’s all about staying one step ahead of cancer.”
