Sorafenib analogue SC‐60 induces apoptosis through the SHP‐1/STAT3 pathway and enhances docetaxel cytotoxicity in triple‐negative breast cancer cells

Recurrent triple‐negative breast cancer (TNBC) needs new therapeutic targets. Src homology region 2 domain‐containing phosphatase‐1 (SHP‐1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP‐1 is STAT3, which is highly activated in TNBC. In this study, we tested a sorafenib analogue SC‐60, which lacks angiokinase inhibition activity, but acts as a SHP‐1 agonist, in TNBC cells. SC‐60 inhibited proliferation and induced apoptosis by dephosphorylating STAT3 in both a dose‐ and time‐dependent manner in TNBC cells (MDA‐MB‐231, MDA‐MB‐468, and HCC1937). By contrast, ectopic expression of STAT3 rescued the anticancer effect induced by SC‐60. SC‐60 also increased the SHP‐1 activity, but this effect was inhibited when the N‐SH2 domain (DN1) was deleted or with SHP‐1 point mutation (D61A), implying that SHP‐1 is the major target of SC‐60 in TNBC. The use of SC‐60 in combination with docetaxel synergized the anticancer effect induced by SC‐60 through the SHP‐1/STAT3 pathway in TNBC cells. Importantly, SC‐60 also displayed a significant antitumor effect in an MDA‐MB‐468 xenograft model by modulating the SHP‐1/STAT3 axis, indicating the anticancer potential of SC‐60 in TNBC treatment. Targeting SHP‐1/p‐STAT3 and the potential combination of SHP‐1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC.