Mayo Clinic Identifies p95HER2 Protein as Key Driver of Resistance to Trastuzumab Deruxtecan in HER2+ Breast Cancer
核心洞察
Mayo Clinic researchers discovered that p95HER2 (搜索), a truncated form of the HER2 (搜索) protein, creates an immune-protected microenvironment that drives resistance to trastuzumab deruxtecan in HER2+ breast cancers.
The study revealed that neratinib effectively blocks p95HER2 (搜索) action and causes complete protein degradation in preclinical models, offering a potential therapeutic solution.
Researchers propose clinical trials combining neratinib with trastuzumab deruxtecan to improve treatment response in patients whose cancers co-express p95HER2 (搜索) and full HER2 (搜索).
Mayo Clinic researchers have identified a critical mechanism underlying resistance to antibody-drug conjugates (ADCs) in HER2 (搜索)-positive breast cancer (搜索), potentially opening new avenues for combination therapies. The study, published in Nature Cancer, reveals how a truncated protein variant drives treatment resistance and proposes a targeted solution using existing therapeutics.
Breakthrough Discovery in ADC Resistance
The research team from Mayo Clinic's Oncoimmune Signaling and Therapeutics Laboratory discovered that p95HER2 (搜索), a shortened version of the HER2 (搜索) protein produced by a subset of HER2+ breast cancers, fundamentally alters treatment response to trastuzumab deruxtecan (T-DXd). While T-DXd has dramatically improved outcomes for many patients with HER2+ breast cancers, some tumors remain resistant to this important therapeutic class.
"While T-DXd has shown remarkable results for many patients, it hasn't worked for everyone with advanced HER2+ breast cancer (搜索)," explains 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. "This indicates that some tumors have built-in resistant mechanisms that prevent the drug from doing its job."
Unique Signaling Mechanism Creates Immune Protection
The study revealed that p95HER2 (搜索) "signals differently" from the full HER2 (搜索) oncoprotein, which proved to be the key to understanding its role in therapy resistance. The truncated protein has a unique ability to induce signals that create an immune-protected microenvironment within cancer cells.
"Our discovery that p95HER2 (搜索) 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," says Dr. Lucas.
Neratinib Shows Promise as Combination Partner
A significant finding from the research was that neratinib, an existing targeted therapy, demonstrates high effectiveness at blocking p95HER2 (搜索) action. The drug not only inhibits the protein but causes its complete degradation in preclinical models.
"In fact, treatment with neratinib results in complete p95HER2 (搜索) degradation, abolishing the protein from the cancer cells in our preclinical models," reports Dong Hu, Ph.D., a research scientist in Laboratory Medicine and Pathology at Mayo Clinic and lead author of the manuscript.
Clinical Translation and Future Directions
Based on these findings, the research team proposes moving forward with clinical trials to evaluate the combination of neratinib with T-DXd in patients with HER2 (搜索)+ early breast cancer (搜索). The goal is to determine whether this combination therapy can improve response rates in cancers that co-express both p95HER2 (搜索) and full HER2.
The researchers acknowledge that this represents just one of many therapeutic combinations under consideration. "No single, one-size-fits-all approach to treatment will work for every patient with HER2+ breast cancer (搜索)," notes Linda McAllister, M.D., Ph.D., a pediatric hematologist/oncologist at Mayo Clinic and co-senior author of the study.
Implications for Personalized Cancer Treatment
The discovery of p95HER2 (搜索)'s role in ADC resistance provides a foundation for developing more personalized treatment approaches. The identification of this specific resistance mechanism offers researchers and clinicians a clear target for intervention.
"Having this new understanding of why T-DXd does not always work helps us to envision next steps toward customized therapies and more cures," says Dr. Lucas. "It's all about staying one step ahead of cancer."
The research establishes a roadmap for future therapeutic development, potentially leading to improved outcomes for patients whose cancers have previously shown resistance to this important class of targeted therapies.