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

Yujie Feng1,2, Miao Fu1, Bowen Zheng1,2,3

  • 1Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China.

NPJ Precision Oncology
|March 7, 2026
PubMed

Insights

Minichromosome maintenance proteins 2 and 5 (MCM2/5) drive resistance to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer. Combining PARPis with CDK4/6 inhibitors resensitizes tumors to treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPis) are crucial in ovarian cancer (OC) treatment.
  • Therapeutic resistance to PARPis like niraparib is a significant clinical obstacle in OC.
  • Understanding novel resistance mechanisms is vital for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of minichromosome maintenance proteins 2 and 5 (MCM2/5) in mediating niraparib resistance in ovarian cancer.
  • To elucidate the molecular pathways driving MCM2/5 upregulation in resistant cells.
  • To evaluate the therapeutic potential of targeting MCM2/5 or its regulatory pathways in combination with PARPis.

Main Methods:

  • RNA sequencing (RNA-seq) to identify differentially expressed genes in niraparib-resistant (NirR) OC cells.
  • Co-immunoprecipitation to assess MCM2/5 complex interaction.
  • Genetic manipulation (knockdown and overexpression) of MCM2/5 to determine functional effects.
  • Pharmacological inhibition of CDK4/6 pathway.
  • In vitro and in vivo preclinical models of ovarian cancer.

Main Results:

  • Niraparib-resistant OC cells exhibit significantly upregulated MCM2 and MCM5 expression.
  • Enhanced MCM2/5 interaction correlates with increased proliferation and homologous recombination repair.
  • MCM2/5 knockdown resensitizes resistant cells to niraparib; overexpression confers resistance.
  • MCM2/5 upregulation is driven by E2F1 transcription factor, activated by the CDK4/6-RB pathway.
  • Combined inhibition of CDK4/6 and niraparib synergistically suppresses NirR tumor growth.

Conclusions:

  • The MCM2/5 complex is a key mediator of PARPi resistance in ovarian cancer.
  • Transcriptional regulation of MCM2/5 by E2F1 via the CDK4/6-RB pathway is a critical resistance mechanism.
  • Combining PARPis with CDK4/6 inhibitors represents a promising therapeutic strategy to overcome PARPi resistance in OC.

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