Exploring TAK-285: A Promising HER2/EGFR Inhibitor with Enhanced CNS Penetration in Rats

A significant portion of individuals with metastatic breast cancer that overexpresses HER2 develop brain metastases, and there is an urgent need for treatments effective after radiotherapy. Current HER2-targeted therapies have limited efficacy against brain metastases, possibly due to poor brain penetration. This study examines the permeability and brain penetration of TAK-285, a new oral dual HER2/EGFR inhibitor, compared to existing drugs lapatinib and neratinib.

Utilizing the Caco-2 cell model, TAK-285 demonstrated high permeability, not affected by efflux pumps, unlike lapatinib and neratinib, which showed lower permeability and were identified as efflux pump substrates. In a rat model with an intact blood-brain barrier, TAK-285 had a notably higher brain-to-plasma area under the curve (AUC) ratio compared to lapatinib and neratinib.

The findings suggest that TAK-285, unlike other receptor tyrosine kinase inhibitors, is not a substrate for efflux transporters, potentially offering a distinct advantage in treating brain lesions associated with HER2- or EGFR-dependent tumors. The drug may also avoid resistance mechanisms linked to efflux transporters.