A University of Liverpool study has uncovered a key mechanism driving cancer invasion and drug resistance in HER2-positive breast cancer, one of the most aggressive forms of the disease. The research reveals a novel 'crosstalk' between HER2 and αVβ6 integrin, two proteins known to independently influence cancer outcomes, and how this interaction is disrupted in trastuzumab-resistant cells.
The study, led by Dr. Mark Morgan, Senior Lecturer in Molecular & Clinical Cancer Medicine, used advanced proteomic analysis to demonstrate that when αVβ6 integrin is activated, it recruits HER2 along with a network of molecules including RAB5, RAB7A, and GDI2. This network facilitates direct communication between αVβ6 and HER2, controlling their movement within cells and triggering signals that drive cancer cell invasion.
Disruption of the Crosstalk in Trastuzumab Resistance
In trastuzumab-resistant breast cancer cells, this intricate network breaks down due to the loss of GDI2, a key regulator. This disruption severs the αVβ6-HER2 connection, causing the cancer to adapt and become more invasive through alternative pathways. Consequently, drugs designed to block αVβ6 or HER2 are no longer effective in preventing cancer invasion, highlighting a critical shift in how tumor cells overcome targeted therapy.
Clinical Implications and Biomarker Potential
The study's findings also link these molecular interactions to patient outcomes. Higher levels of GDI2 are associated with better survival rates, while αVβ6 expression predicts an increased likelihood of relapse after trastuzumab treatment. This makes αVβ6 a promising biomarker for identifying patients at higher risk of treatment failure and a potential target for therapies to overcome resistance.
Therapeutic Strategies
"These findings are pivotal to understanding how breast cancer invades tissue, but also how it becomes resistant to targeted treatments," said Dr. Morgan. "The discovery of this αVβ6-HER2 crosstalk mechanism, and its disruption in resistant cells, opens up new avenues for therapeutic interventions."
Targeting the RAB5/RAB7A/GDI2 module or restoring its normal function may prevent or delay the onset of resistance in HER2-positive breast cancers. Furthermore, monitoring αVβ6 expression in patients could help predict treatment outcomes and guide personalized therapies.
Future Directions
Dr. Morgan added, "The study also found invasion of trastuzumab resistant cells is no-longer stopped by reagents that block αVβ6 function. However, these resistant cells have very high levels αVβ6 on their surface. So, we now want to explore developing new drugs that specifically target cells with high αVβ6 levels and either deliver a lethal warhead, or re-programme them to be targeted by the patient's own immune system."
The research provides a potential roadmap for developing new strategies to counteract drug resistance in HER2-positive breast cancer, offering hope for more effective and personalized treatments.
