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

Akitomo Inoue1, Hidetatsu Outani1, Yoshinori Imura1

  • 1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Cancer Science
|January 10, 2025
PubMed

Insights

Epithelioid sarcoma (EpS) cells lacking INI1 protein rely on the AURKA/PLK1/CDC25C pathway for growth. Inhibiting this axis with alisertib shows therapeutic promise for EpS treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epithelioid sarcoma (EpS) is an aggressive soft tissue sarcoma lacking effective treatments.
  • INI1 deficiency is a hallmark of EpS, but its functional consequences remain unclear.
  • The aurora kinase A (AURKA)/polo-like kinase 1 (PLK1)/cell division cycle 25C (CDC25C) axis is crucial for cell cycle progression.

Purpose of the Study:

  • To investigate the role of INI1 loss in EpS pathogenesis.
  • To explore the association between INI1 deficiency and the AURKA/PLK1/CDC25C axis.
  • To evaluate the therapeutic potential of targeting this axis in EpS.

Main Methods:

  • INI1 reintroduction in EpS cell lines.
  • siRNA-mediated silencing of AURKA.
  • Treatment with alisertib, a selective AURKA inhibitor.
  • Cell proliferation assays, cell cycle analysis, apoptosis assays, and xenograft studies.

Main Results:

  • INI1 reintroduction reduced EpS cell proliferation and tumorigenicity by downregulating AURKA/PLK1/CDC25C.
  • AURKA silencing or inhibition with alisertib suppressed EpS cell growth and induced cell cycle arrest and apoptosis.
  • Alisertib demonstrated significant efficacy in reducing xenograft tumor growth, dependent on INI1 deficiency.
  • EpS cells with INI1 loss exhibit dependency on the AURKA/PLK1/CDC25C axis.

Conclusions:

  • INI1 loss in EpS drives tumor growth through sustained activation of the AURKA/PLK1/CDC25C pathway.
  • Targeting the AURKA/PLK1/CDC25C axis represents a promising therapeutic strategy for epithelioid sarcoma.
  • Alisertib shows potential as a targeted therapy for INI1-deficient EpS.
Keywords:
alisertibaurora kinase Aepithelioid sarcomapolo‐like kinase 1soft tissue sarcoma

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