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All roads lead to mitosis: A common requirement for DNA replication stress-dependent and -independent killing of

Sebastian Omar Siri1, Ariel Abramovici Blasco1, Ginette Moyano1

  • 1Cell Cycle and Genome Stability Laboratory, Fundación Instituto Leloir, Buenos Aires C1405 BWE, Argentina; Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1405 BWE, Argentina.

Mutation Research. Reviews in Mutation Research
|August 1, 2025
PubMed

Insights

Targeting BRCA1/2-deficient tumors with PARP inhibitors (PARPi) can lead to resistance. This review explores alternative treatments, including ROCK and PLK1 inhibitors, that may overcome resistance by inducing cell death independently of replication stress or chromosome instability.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • BRCA1 and BRCA2 (Breast cancer genes 1 and 2) mutations lead to early-onset tumors.
  • Poly (ADP-ribose) polymerase inhibitors (PARPi) selectively target BRCA1/2-deficient tumors but can cause treatment resistance.
  • PARPi induce cell death via replication stress and chromosome instability, including micronuclei accumulation.

Purpose of the Study:

  • To review alternative therapeutic strategies for BRCA1/2-deficient tumors.
  • To identify treatments that selectively kill cancer cells while minimizing side effects.
  • To explore mechanisms of cell death that circumvent PARPi resistance.

Main Methods:

  • Literature review of existing and emerging cancer therapies.
  • Analysis of treatment-induced cell death pathways in BRCA1/2-deficient models.
  • Comparison of replication stress-dependent and -independent cell killing mechanisms.

Main Results:

  • PARPi efficacy is linked to replication stress and chromosome instability.
  • Alternative treatments are being investigated for BRCA1/2-deficient tumors.
  • Rho-kinase (ROCK) and Polo-like kinase 1 (PLK1) inhibitors show potential for RS-independent, MN-independent cell killing.

Conclusions:

  • Alternative therapies targeting ROCK and PLK1 may offer novel strategies against BRCA1/2-deficient tumors.
  • RS-independent and MN-independent cell killing mechanisms could prevent or delay treatment resistance.
  • Targeting distinct cell death pathways may overcome limitations of current PARPi treatments.
Keywords:
BRCA1/2PARPPLK1, ROCKchromosome instabilitysynthetic lethality

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