New Research Uncovers Resistance Mechanism in HER2+ breast Cancer, Paving Way for Targeted Therapies
A recent study has identified a key factor contributing to treatment resistance in some patients with HER2-positive breast cancer, offering a potential new avenue for developing more effective, personalized therapies.
Researchers at the Mayo Clinic, publishing their findings in Nature Cancer, have discovered that a truncated form of the HER2 protein, known as p95HER2, plays a significant role in limiting the effectiveness of antibody-drug conjugate (ADC) therapies like trastuzumab deruxtecan (T-DXd). While ADCs have dramatically improved outcomes for many HER2+ breast cancer patients, a subset still experiences treatment failure.
The research team, led by Dr. Peter Lucas, found that p95HER2 differs from the full-length HER2 protein in its signaling pathways within cancer cells. This difference alters the tumor microenvironment, creating a protective shield that hinders the immune system’s ability to attack the cancer. Specifically, p95HER2 appears to foster an immune-protected environment, allowing tumors to evade the effects of T-DXd.
“Our finding shows that p95HER2 can create a protected immune microenvironment, allowing tumors to resist treatment,” explained Dr. Lucas.
Importantly,the study also identified a potential strategy to overcome this resistance. The researchers demonstrated that the drug neratinib can effectively block the activity of p95HER2, and even lead to its complete breakdown within cancer cells in laboratory models.
“Treatment with neratinib fully eliminates the p95HER2 protein from cancer cells, suggesting significant potential for therapeutic combinations,” stated Dr. Dong Hu, lead author of the study.
Based on these promising preclinical results, the Mayo Clinic team is proposing clinical trials to evaluate the combination of neratinib and T-DXd in patients with early-stage HER2+ breast cancer. The goal is to determine if this combination can improve treatment response in tumors that express both HER2 and p95HER2.
Researchers emphasize that a personalized approach to treatment remains crucial. “There is no one-size-fits-all solution for all HER2+ breast cancer patients. However, identifying the role of the p95HER2 protein provides a clear direction for the growth of tailored therapies,” noted Dr. Linda McAllister,a co-author of the study.
this discovery represents a significant advancement in understanding the complexities of HER2+ breast cancer and offers hope for anticipating and overcoming treatment resistance, ultimately leading to improved outcomes for patients.
