Abstract 1959: Therapeutic rationale for SHP2 phosphatase inhibitors: Targeting drug-resistant breast cancer via blockade of FGFR1 signaling
Authors: Hao Chen, Sheng Zhang, Zhong-Yin Zhang, Michael Keith Wendt
Journal: Cancer Research (2018)

Abstract Human epidermal growth factor receptor-2 (Her2) amplified breast cancer represents ~25% of breast cancer. Clinically used tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, are capable of blocking Her2 signaling and provide therapeutic benefits. Unfortunately, resistance to TKIs is reducing survival of patients. Hence, there is a critical need for novel therapies targeting drug-resistant breast cancer. Expression of fibroblast growth factor receptor-1 (FGFR1) can be induced by acquired resistance to lapatinib. Also, FGFR1 signaling is a critical growth factor receptor signaling in drug resistance network. Src Homology Phosphatase-2 (SHP2) is a protein tyrosine phosphatase that facilitates growth factor receptor signaling and is strongly linked with cancer progression. Currently, there are two types of inhibitors targeting SHP2, one with allosteric binding mechanism (SHP099) and one with active-site mechanism (11a-1). However, there is still a mechanistic gap in knowledge concerning the roles of SHP2 in drug-resistant breast cancer. Our findings support the core hypothesis that SHP2 phosphatase is required for FGFR1 signaling, contributing to drug resistance. First, we stably overexpressed SHP2 and FGFR1 in normal murine-mammary-gland (NMuMG) cells. SHP2 could facilitate FGFR1 signaling driving cell growth. Conversely, pharmacologic inhibition of SHP2 could partially reduce phosphorylation of FRS2, AKT and ERK, downstream of FGFR1. Next, we identified the growth-inhibitory effects of SHP2 inhibitors in Her2 transformed cells that are sensitive (HMLE-HER2) and resistant (HMLE-HER2-LapR) to TKIs. Both SHP2-targerting compounds had significantly improved growth-inhibition effects in 2D growth assays on HMLE-HER2-LapR cells, which overexpress FGFR1. Both SHP2 inhibitors also inhibited the growth of SK-BR-3 and ZR-75-1 cells. While in 3D growth assays with the same cell lines, the growth inhibition effects were much better compared with 2D growth assays. To better identify whether TKIs-resistant cells could be targeted by SHP2 inhibitors, we assessed whether SHP2 inhibition could block signaling recovery after neratinib treatments. The results showed that both of inhibitors could significantly delay p-AKT and p-ERK after neratinib treatments. To further identify potential therapeutic application of SHP2 inhibitors, we assessed the efficacy of 11a-1 alone, or in combination with neratinib. To this end, we found that 11a-1 could decrease growth and migration of TKIs-resistant cells when used in combination with neratinib. In summary, continued understanding of the detailed mechanisms of SHP2 in FGFR1 signaling and continued development of compounds capable of inhibition SHP2 function may provide a therapeutic strategy for targeting SHP2 in combination with TKIs to prolong patient response rates in this subtype of breast cancer. Citation Format: Hao Chen, Sheng Zhang, Zhong-Yin Zhang, Michael Keith Wendt. Therapeutic rationale for SHP2 phosphatase inhibitors: Targeting drug-resistant breast cancer via blockade of FGFR1 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1959.