Despite the initial effectiveness of HER2-targeted therapies, a major clinical challenge remains the development of acquired resistance, where the tumor finds ways to evade the effects of the treatment over time. The mechanisms behind this resistance are complex and multifaceted, often involving alterations to the HER2 receptor itself or the activation of alternative signaling pathways within the cancer cell. Understanding these evasive maneuvers is crucial for the development of subsequent therapeutic strategies, ensuring that patients continue to have viable options as their disease evolves.

One common mechanism involves the presence of a truncated receptor form called p95HER2, which lacks the binding site for Trastuzumab but retains its signaling capacity, rendering the tumor resistant to that specific drug. Other pathways, such as the activation of PI3K/AKT signaling or the increased expression of other HER family receptors like HER3, can compensate for the HER2 blockade. The complex biology of resistance to HER2-directed agents highlights the need for continuous research and the rapid translation of findings into clinical practice to improve long-term disease control and progression-free survival rates.

To overcome this, researchers are exploring combination therapies that simultaneously target multiple points in the signaling network, such as pairing HER2 inhibitors with agents that block PI3K/AKT. Furthermore, small molecule tyrosine kinase inhibitors (TKIs), like Lapatinib and Tucatinib, are capable of passing through the cell membrane and acting directly on the receptor's interior, kinase domain, and can also penetrate the blood-brain barrier. The strategic sequencing of these different classes of drugs, including ADCs, TKIs, and monoclonal antibodies, represents the current cutting edge in managing resistance and maintaining clinical benefit for patients.

FAQ

• What is p95HER2? It is a shortened (truncated) version of the HER2 receptor that lacks the extracellular portion where Trastuzumab binds, making cancer cells that express it resistant to Trastuzumab but sometimes still sensitive to tyrosine kinase inhibitors.

• Can resistance be overcome? Yes, resistance is frequently managed by switching to a different mechanism of action, such as moving from monoclonal antibodies to Antibody-Drug Conjugates (ADCs) or small molecule tyrosine kinase inhibitors (TKIs).