Alisertib inhibits acute myeloid leukemia cell growth by inhibiting STAT3 activation

Abstract

Aurora kinase A (AURKA) plays critical roles in the cell cycle. Its oncogenic functions have been identified in various types of cancer. However, its role in acute myeloid leukemia (AML) has not been extensively explored. Alisertib, a selective AURKA inhibitor, is currently being evaluated in clinical trials for the treatment of several cancers. In this study, we aimed to assess the efficacy of alisertib and elucidate its molecular mechanisms in AML cells. In vitro and in vivo experiments were conducted using western blotting and immunocytochemistry, respectively, to identify the effects of alisertib on two AML cell lines (KG-1 and MOLM-13). Primary cells from three patients with AML were used to examine the response to alisertib treatment. The results showed alisertib significantly reduced Thr288 phosphorylation of AURKA in both KG-1 and MOLM-13 cell lines. Interestingly, it selectively inhibited STAT3 phosphorylation at Tyr705, but not at Ser727. Notably, alisertib significantly decreased interleukin-6-induced nuclear pTyr705-STAT3 levels after short-term treatment, while also affecting the expression of downstream c-Myc. In addition to these in vitro findings, in vivo xenograft model using KG-1 cells showed significant tumor growth retardation accompanied by pTyr705-STAT3 inhibition following alisertib treatment. In primary AML patient cells, we observed a consistent trend in the alisertib-induced reduction of pTyr705-STAT3 and cell growth inhibition. In conclusion, AURKA and alisertib are promising therapeutic targets and treatment options for AML.

Keywords: AML; AURKA; Alisertib; STAT3; c-Myc.