Abstract P6-20-17: Targeting SHP2 for the treatment of HER2-positive breast cancer

Approximately 20% of breast cancer (BC) is caused by overexpression of the human epidermal growth factor receptor 2 (HER2). As a result, several antibody-based and small molecule-based anti-HER2 therapies have been developed. These drugs have benefited BC patients by improving overall survival and quality of life. However, development of resistance and disease recurrence have been the major clinical challenges. One way to overcome these clinical problems is to develop alternative therapeutic strategies. Multiple lines of evidence show that targeting the Src homology phosphotyrosyl phosphatase 2 (SHP2) in HER2-positive BC may prove beneficial both in treatment-naive and anti-HER2 therapy-resistant forms of the disease. For instance, silencing SHP2 expression in HER2-positive breast cancer cells or conditional knockout in ErbB2 transgenic mice blocks HER2 overexpression and associated signaling, leading to loss of cell transformation and tumorigenesis. To test the clinical translational significance of SHP2 targeting, we have invented a specific small molecule SHP2 inhibitor named WGMDY (US 9,932,288) that has shown promising anti-cancer effects. The results obtained so far show that inhibition of SHP2 with WGMDY blocks HER2 expression, suppresses cell proliferation and anchorage independent growth, and induces regression of preformed xenograft tumors. These findings suggest that SHP2 might be an excellent drug target for HER2-positive BC and WGMDY has a promising potential to serve as a lead compound for developing anti-SHP2 drugs. Citation Format: Agazie Y, Hartman Z. Targeting SHP2 for the treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-17.