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. [ABSTRACT FROM AUTHOR]