AURKA/PLK1/CDC25C Axis as a Novel Therapeutic Target in INI1-Deficient Epithelioid Sarcoma.

Abstract

Effective therapeutic strategies for epithelioid sarcoma (EpS), a high-grade soft tissue sarcoma characterized by loss of integrase interactor 1 (INI1), have not yet been developed. The present study therefore investigated the association between INI1 loss and upregulation of the aurora kinase A (AURKA)/polo-like kinase 1 (PLK1)/cell division cycle 25C (CDC25C) axis, as well as the therapeutic relevance of this axis in EpS. Notably, our findings showed that the reintroduction of INI1 in VA-ES-BJ cells significantly reduced proliferation, mitigated tumorigenicity, and negatively regulated the expression of AURKA and its downstream effectors, as well as the activation of PLK1 and CDC25C. These results suggest that INI1 deficiency enhanced EpS growth by upregulating the AURKA/PLK1/CDC25C axis. AURKA silencing using siRNAs inhibited VA-ES-BJ and Asra-EPS cell proliferation by inactivating PLK1 and CDC25C. Alisertib, a selective AURKA inhibitor, exerted markedly greater antiproliferative effects on EpS cells than on normal human dermal fibroblasts, and these effects were dependent on INI1 deficiency. Inhibition of AURKA activity by alisertib induced G2/M cell cycle arrest and apoptosis via the inactivation of AURKA downstream effectors in EpS cells. Alisertib also significantly decreased VA-ES-BJ xenograft tumor growth. Taken together, our findings revealed that INI1 loss in EpS cells enhances the expression of AURKA and its downstream effectors and persistently activates PLK1 and CDC25C mediated by AURKA, making the cells reliant on the AURKA/PLK1/CDC25C axis. Therefore, the AURKA/PLK1/CDC25C axis activated by INI1 deficiency could serve as a novel therapeutic target for this devastating disease.