The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells

Chun-Yu Liu,Ka-Yi Lau,Wan-Lun Wang,Chia-Han Lee,Ming-Huang Chen,Pei-Yi Chu,Tzu-Ting Huang,Jung-Chen Su,Ling-Ming Tseng,Chung-Wai Shiau,Chun-Teng Huang,Tzu-I Chao,Wen-Chun Tsai,Kuen-Feng Chen

doi:10.1038/emm.2017.114

Abstract

Triple-negative breast cancer (TNBC) remains difficult to treat and urgently needs new therapeutic options. Nintedanib, a multikinase inhibitor, has exhibited efficacy in early clinical trials for HER2-negative breast cancer. In this study, we examined a new molecular mechanism of nintedanib in TNBC. The results demonstrated that nintedanib enhanced TNBC cell apoptosis, which was accompanied by a reduction of p-STAT3 and its downstream proteins. STAT3 overexpression suppressed nintedanib-mediated apoptosis and further increased the activity of purified SHP-1 protein. Moreover, treatment with either a specific inhibitor of SHP-1 or SHP-1-targeted siRNA reduced the apoptotic effects of nintedanib, which validates the role of SHP-1 in nintedanib-mediated apoptosis. Furthermore, nintedanib-induced apoptosis was attenuated in TNBC cells expressing SHP-1 mutants with constantly open conformations, suggesting that the autoinhibitory mechanism of SHP-1 attenuated the effects of nintedanib. Importantly, nintedanib significantly inhibited tumor growth via the SHP-1/p-STAT3 pathway. Clinically, SHP-1 levels were downregulated, whereas p-STAT3 was upregulated in tumor tissues, and SHP-1 transcripts were associated with improved disease-free survival in TNBC patients. Our findings revealed that nintedanib induces TNBC apoptosis by acting as a SHP-1 agonist, suggesting that targeting STAT3 by enhancing SHP-1 expression could be a viable therapeutic strategy against TNBC.

Highlights

The results demonstrated that nintedanib enhanced Triple-negative breast cancer (TNBC) cell apoptosis, which was accompanied by a reduction of p-Signal transducer and activator of transcription 3 (STAT3) and its downstream proteins
Nintedanib exerts an anti-proliferative effect on TNBC cell lines To examine the anti-tumor ability of nintedanib on human TNBC cells, we first tested the effects of nintedanib on cell growth in three TNBC cell lines: MDA-MB-231, MDA-MB-468 and HCC-1395
The results indicated that nintedanib significantly increased the differential apoptotic effects (Figure 1b) in these TNBC cells in a dose-dependent manner

Summary

Introduction

Triple-negative breast cancer (TNBC) is distinguished by the paradox of a favorable chemotherapeutic response but higher rates of early recurrence and worse outcomes compared to non-TNBC as well as its heterogeneous molecular profiling.[1,2] Currently, there is no approved targeted therapy for TNBC despite the suggestion of various strategies targeting the heterogeneous molecular pathways or subtypes, such as PARP inhibitors for BRCA-deficient subtypes and anti-androgen molecules for androgen receptor-expressing subtypes.[1,2] The identification of novel therapeutic targets and the development of new agents for TNBC remains a challenging task and represents an unmet need.Src homology region 2 domain containing phosphatase 1 (SHP-1) is a non-receptor protein tyrosine phosphatase (PTP) and a tumor suppressor gene in different cancer types, including breast cancer.[3].

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