Small-molecule inhibitor of Fam20C in combination with paclitaxel suppresses tumor growth by LIF-JAK2/STAT3-modulated apoptosis in triple-negative breast cancer

Abstract

BackgroundTriple negative breast cancer (TNBC) is a strongly proliferative, relapse prone, high-mortality subtype of breast cancer. Due to the lack of effective therapeutic targets, the current clinical treatment is still dominated by chemotherapeutic drugs, such as paclitaxel (PTX). Moreover, Fam20C kinase inhibitor (3R) has recently been reported to inhibit TNBC growth. Thus, the objectives of this study were to verify whether the combination therapy with 3R could enhance the efficacy of PTX treatment on TNBC, and to further elucidate their potential synergistic mechanisms. MethodsThe inhibitory effect on TNBC cell viability was verified by the MTT assay, and the effect of drug combination on apoptosis was analyzed by flow cytometry. The mechanism of action of the drug combination was validated based on transcriptome analyses and western blot (WB) analysis. Xenograft mouse models were used to verify the therapeutic efficacy of PTX+3R in vivo by immunohistochemistry and WB analysis. Significant findingsFam20C inhibitor (3R) enhanced the inhibitory effect of PTX on the viability and proliferation of MDA-MB-231 and BT-549 cells, and their combination significantly promoted cell apoptosis. In addition, we found that 3R reduced the expression of leukemia inhibitor factor (LIF). 3R and PTX limit the phosphorylation activation of signal transducer and activator of translation 3 (STAT3). Finally, immunohistochemical staining showed that combined treatment with 3R and PTX inhibited tumor growth in an ectopic tumor model of MDA-MB-231 cells in nude mice.