Development of a more penetrating HER2-positive Breast Cancer Tumor Model and Testing Efficacy of SHP2 Targeting with an Active-Site Inhibitor

Advanced stage HER2-positive (HER2+) breast cancer (BC) is very challenging for treatment. These premises justify the need to develop novel targeted therapies that can be used to complement existing anti-HER2 therapies. Accordingly, we investigated the potential of the Src homology phosphotyrosyl phosphatase 2 (SHP2), the master regulator of RTK signaling, for use in advanced stage HER2 + BC. To test this possibility, we first generated a more-penetrating tumor model referred to as ErbB2+;p53 ^−/− . This model exhibited tumor properties reminiscent of advanced stage HER2 + BC. To target SHP2, we used our previously reported active-site SHP2 inhibitor referred to as BPDA2. The results showed suppression of tumor growth in a 20 mg/kg group and complete blockade in a 40 mg/kg group when compared to the placebo. Histopathology analysis showed a locally invasive and highly vascularized tumor with metastasis to the lungs and the liver in the placebo and a non-invasive tumor with undetectable vascularization in the treated mice. Body weight measurement showed no major changes between the placebo and the treated mice, suggesting that BPDA2 is a very well tolerated SHP2 inhibitor. Biochemical analysis of tumor protein extracts showed downregulation of HER2 expression and mitogenic and cell survival signaling. Overall, the results in this study demonstrate that targeting SHP2 with the active-site inhibitor blocks tumorigenesis and metastasis in HER2-positive BC.