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

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. A drug approved to treat pulmonary fibrosis may help kill breast cancer cells that lack the three receptors known to fuel tumor growth. A team in Taiwan led by Kuen-Feng Chen from the National Taiwan University Hospital and Ling-Ming Tseng from the Taipei Veterans General Hospital tested the effects of the multi-kinase inhibitor nintedanib on triple-negative breast cancer in cell culture and in mouse models. They found that the drug reduced the cells' proliferative ability and increased cell death by inducing the expression of an enzyme called SHP-1 that keep down levels of the cancer-promoting protein STAT3. The researchers confirmed the importance of this pathway in patient samples, showing that SHP-1 levels are typically down and STAT3 levels up in tumor tissue. Additionally, patients whose tumors had higher SHP-1 expression generally had better outcomes.