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Abstract P3-10-20: Targeting the tyrosine phosphatase SHP2 is efficacious against HER2-positive breast cancer

Accumulating evidence suggests that the Src homology phosphotyrosyl phosphatase 2 (SHP2) is a bona fide oncogene. These conclusions are primarily based on the positive role of SHP2 in receptor tyrosine kinase (RTK) signaling in multiple systems. Because overexpression of the human epidermal growth factor receptor 2 (HER2) is one of the primary causes of BC, we investigated the potential of SHP2 targeting in this subtype of BC. We have used our recently patented SHP2 inhibitor called WGMDY (US 9,932,288) for targeting SHP2 under cell culture and in vivo conditions. We have also used the recently reported allosteric SHP2 inhibitor called SHP099 particularly in the cell culture studies. We found that HER2-positive BC cells are highly sensitive to SHP2 inhibition with WGMDY as determined by loss of viability in 2D, transformation in soft agar, and cancer stem cell properties in suspension cultures. Similar results were obtained with SHP099 albeit at a reduced rate. Analysis of protein and RNA extracts showed inhibition of the Ras-ERK and the PI3K-Akt signaling pathways by WGMDY, but SHP099 tend to activate Akt signaling. In addition, WGMDY blocked overexpression of the HER2 protein in HER2-positive BC cells. As such, we focused on WGMDY for the in vivo efficacy studies. The results showed that WGMDY induces regression of preformed tumors in a concentration dependent manner. Histopathology analyses of tumors showed induction of necrosis in treated samples. Hence, WGMDY has a promising anti-cancer effects in HER2-positive BC. Citation Format: Yehenew Agazie, Zachary Hartman. Targeting the tyrosine phosphatase SHP2 is efficacious against HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-20.