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<p>Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies with poor clinical outcomes and limited treatment options. Brentuximab vedotin (BV), a CD30-targeted antibody–drug conjugate, has shown efficacy in CD30-positive PTCLs but is frequently associated with incomplete responses and relapse. To enhance its therapeutic effect, we previously identified defects in spindle assembly checkpoint (SAC) regulation as key sensitizers to BV via a genome-wide CRISPR–Cas9 screen. Building on this, we conducted a cell cycle–focused chemical screen and identified polo-like kinase 1 (PLK1) inhibitors as potent synergistic partners for BV. Among them, volasertib consistently enhanced BV-induced cytotoxicity across multiple CD30-positive PTCL cell lines. Mechanistically, the BV–volasertib combination induced sustained mitotic arrest through activation of the SAC, followed by mitotic catastrophe, apoptosis, and DNA damage. This SAC dependence was further supported by the use of a selective Mps1 inhibitor. Importantly, the combination significantly suppressed tumor growth and prolonged survival in both cell line–derived and patient-derived xenograft (PDX) models. These findings underscore the therapeutic potential of combining BV with PLK1 inhibition, and highlight SAC activation as a key mechanism to overcome therapeutic resistance in CD30-positive PTCL.</p>

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PLK1 inhibition enhances Brentuximab vedotin efficacy in CD30-positive T-cell lymphoma via spindle assembly checkpoint activation

  • 期刊论文

  • 发表日期：

    2026年7月13日

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  • Yuto Mori,
  • Keito Suto,
  • Norio Takei,
  • Keito Yokoyama,
  • Masahiro Chiba,
  • Takashi Ishio,
  • Hideki Goto,
  • Tomoyuki Endo,
  • Hiroo Hasegawa,
  • Michiyuki Maeda,
  • Satoko Otsuguro,
  • Katsumi Maenaka,
  • Takanori Teshima,
  • Yibin Yang,
  • Masao Nakagawa

摘要

Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies with poor clinical outcomes and limited treatment options. Brentuximab vedotin (BV), a CD30-targeted antibody–drug conjugate, has shown efficacy in CD30-positive PTCLs but is frequently associated with incomplete responses and relapse. To enhance its therapeutic effect, we previously identified defects in spindle assembly checkpoint (SAC) regulation as key sensitizers to BV via a genome-wide CRISPR–Cas9 screen. Building on this, we conducted a cell cycle–focused chemical screen and identified polo-like kinase 1 (PLK1) inhibitors as potent synergistic partners for BV. Among them, volasertib consistently enhanced BV-induced cytotoxicity across multiple CD30-positive PTCL cell lines. Mechanistically, the BV–volasertib combination induced sustained mitotic arrest through activation of the SAC, followed by mitotic catastrophe, apoptosis, and DNA damage. This SAC dependence was further supported by the use of a selective Mps1 inhibitor. Importantly, the combination significantly suppressed tumor growth and prolonged survival in both cell line–derived and patient-derived xenograft (PDX) models. These findings underscore the therapeutic potential of combining BV with PLK1 inhibition, and highlight SAC activation as a key mechanism to overcome therapeutic resistance in CD30-positive PTCL.