Countermeasures after tucatinib/tucatinib resistance

Tucatinib/Tucatinib (Tucatinib) selectively inhibits the tyrosine kinase activity of the HER2 receptor, thereby blocking HER2-dependent signaling pathways, including the PI3K/AKT and MAPK pathways. However, similar to other targeted drugs, resistance may still occur after long-term treatment. HER2-positive breast cancer cells have strong genetic instability. After months or years of targeted inhibition, they will escape the effects of drugs through a variety of mechanisms, leading to disease progression.

Common resistance mechanisms include:HER2 structural mutations, HER3 overexpression, activation of downstream signaling pathways (such as PIK3CA, AKT mutations), and changes in the tumor microenvironment. Some of these patients will also experience a reduction in HER2 gene copies or transform into a HER2-negative phenotype, resulting in a weakened response to HER2 inhibitors. Faced with this situation, clinicians usually re-evaluate the patient's molecular characteristics through genetic testing or tissue biopsy, and then develop individualized treatment plans.

For patients with acquired drug resistance, foreign treatment strategies have gradually become diversified. The first is to replace drugs with deeper target levels, such as using antibody-drug conjugates (ADC) trastuzumab drutecan (Enhertu, T-DXd) or trastuzumab-metansin conjugate (T-DM1). These drugs achieve the killing of drug-resistant cells by delivering cytotoxic carriers. Secondly, combination treatment strategies can be considered, such as combining tucatinib with a PI3K inhibitor (Alpelisib) or a CDK4/6 inhibitor (Abemaciclib) to block multiple survival pathways simultaneously.

In addition, treatment strategies are more complex for patients with drug resistance after brain metastasis. Although tucatinib has good blood-brain barrier penetration, progression may still occur in focal lesions in the brain. At this time, local radiotherapy or SRS precision radiation can be combined with the continued use of systemic HER2-targeted drugs to delay the progression of drug resistance.

Reference materials:https://www.tukysa.com/