Harnessing the Power of TAS0728: A Dual Approach to HER2-Targeted Therapy in Overexpressing Tumor Models

HER2 is recognized as a significant target for treating breast and gastric cancers. While treatments targeting HER2 are accessible, they are often combined with chemotherapy. Recent findings hint at the potential of HER2-targeting therapies without chemotherapy. TAS0728, now known as TPC-107, is a novel, orally administered inhibitor that specifically targets HER2 without affecting EGFR. It has shown strong activity against HER2 mutations and overexpression in cells. The study reports that TAS0728 has potent antitumor effects, both on its own and when combined with HER2-targeting antibodies, in HER2-amplified tumor models.

In the study, TAS0728 was given to mice for 14 days to determine its plasma concentration and pharmacokinetic properties. The drug was also administered to mice with N87 xenografts to assess its pharmacodynamic effects, with tumor tissues examined through Western blot analysis. The drug's antitumor efficacy was tested in BT-474 and N87 xenograft models as a single agent, and its combination with trastuzumab or T-DM1 was studied in the 4-1ST xenograft model. The study monitored tumor volume and body weight changes.

The results indicate that TAS0728 has favorable oral pharmacokinetics and significantly inhibits HER2 and HER3 phosphorylation in tumor tissues. TAS0728 was found to be highly effective at doses of 30 and 60 mg/kg/day in the N87 and BT474 models, with minimal impact on body weight. Furthermore, TAS0728 at 15 mg/kg/day significantly enhanced the antitumor effects of trastuzumab or T-DM1 in the 4-1ST model.

The study concludes that TAS0728 is effective as a standalone treatment and when combined with HER2-targeting antibodies such as trastuzumab and T-DM1, providing a basis for its use in treating tumors with HER2 overexpression.

Reference: Irie H, Oguchi K, Ito K, et al. "TAS0728, a HER2-selective covalent inhibitor, shows significant antitumor activity as a monotherapy and in combination with anti-HER2 antibodies in models of HER2-overexpressing tumors." Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B179.