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<p>Resistance to poly (ADP-ribose) polymerase inhibitors (PARPis) like niraparib represents a major therapeutic challenge in ovarian cancer (OC). This study elucidates a novel resistance mechanism driven by the minichromosome maintenance proteins 2 and 5 (MCM2/5). In niraparib-resistant (NirR) OC cells, RNA-seq revealed upregulation of MCM2 and MCM5, which was functionally linked to enhanced proliferation and homologous recombination repair. Co-immunoprecipitation confirmed strengthened MCM2/5 interaction in NirR cells. Genetic knockdown of MCM2/5 resensitized NirR cells to niraparib, while their overexpression conferred resistance in parental cells. Mechanistically, the upregulation of MCM2/5 was transcriptionally regulated by the E2F1 transcription factor, activated via the CDK4/6-RB pathway. Consequently, pharmacological inhibition of CDK4/6 downregulated MCM2/5 expression and, when combined with niraparib, synergistically suppressed NirR tumor growth both in vitro and in vivo. Our findings identify the MCM2/5 complex as a critical mediator of PARPi resistance and establish the therapeutic potential of combining PARPis with CDK4/6 inhibitors to overcome this resistance in ovarian cancer.</p>

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CDK4/6i reverse PARPi resistance by targeting the E2F1- MCM2/5 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月7日

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  • Yujie Feng,
  • Miao Fu,
  • Bowen Zheng,
  • Fanzhuoran Lou,
  • Xintian Huang,
  • Xiaowen Xie,
  • Weijuan Tan,
  • Quan Chen,
  • Wenqing Zhang,
  • Yongxiang Hong,
  • Kaiyi Rong,
  • Huibo Shi,
  • Tianhui Hu,
  • Li Xiao

摘要

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPis) like niraparib represents a major therapeutic challenge in ovarian cancer (OC). This study elucidates a novel resistance mechanism driven by the minichromosome maintenance proteins 2 and 5 (MCM2/5). In niraparib-resistant (NirR) OC cells, RNA-seq revealed upregulation of MCM2 and MCM5, which was functionally linked to enhanced proliferation and homologous recombination repair. Co-immunoprecipitation confirmed strengthened MCM2/5 interaction in NirR cells. Genetic knockdown of MCM2/5 resensitized NirR cells to niraparib, while their overexpression conferred resistance in parental cells. Mechanistically, the upregulation of MCM2/5 was transcriptionally regulated by the E2F1 transcription factor, activated via the CDK4/6-RB pathway. Consequently, pharmacological inhibition of CDK4/6 downregulated MCM2/5 expression and, when combined with niraparib, synergistically suppressed NirR tumor growth both in vitro and in vivo. Our findings identify the MCM2/5 complex as a critical mediator of PARPi resistance and establish the therapeutic potential of combining PARPis with CDK4/6 inhibitors to overcome this resistance in ovarian cancer.