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Genome destabilization-associated phenotypes arising as a consequence of therapeutic treatment are suppressed by

Mafuka Suzuki1,2, Haruka Fujimori1,2, Kakeru Wakatsuki1

  • 1Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan.

Plos One
|January 27, 2023
PubMed

Insights

The PARP inhibitor Olaparib suppresses therapeutic resistance and metastasis in cancer cells surviving DNA damage. It reduces genomic instability and cell migration, enhancing cancer cell death and DNA repair.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cancer therapies like radiation and chemotherapy induce DNA double-strand breaks (DSBs) to kill cancer cells.
  • Therapeutic resistance and metastasis are significant challenges in cancer treatment, often emerging after treatment.
  • The mechanisms underlying DSB resistance and potential suppression strategies remain incompletely understood.

Purpose of the Study:

  • To investigate how cancer cells develop resistance to DNA double-strand breaks (DSBs) induced by treatments.
  • To explore the role of genomic instability and cytosolic DNA in promoting therapeutic resistance and metastasis.
  • To evaluate the efficacy of the PARP inhibitor Olaparib in suppressing these resistance mechanisms.

Main Methods:

  • Induction of DSBs in cancer cells using camptothecin (CPT) and radiation.
  • Assessment of genome stability and DNA damage response pathways.
  • Analysis of cytosolic DNA accumulation and cGAS/STING pathway activation.
  • Evaluation of cell migration assays as a measure of metastatic potential.
  • Treatment with the PARP inhibitor Olaparib to assess its suppressive effects.

Main Results:

  • DSBs induced by CPT and radiation destabilize the genome in surviving cancer cells, leading to resistance.
  • Accumulated cytosolic DNA activates the cGAS/STING pathway, promoting cell migration and potential metastasis.
  • Olaparib treatment significantly suppressed genomic destabilization and reduced DSB recognition by Rad51.
  • Olaparib enhanced the DNA damage response and increased cancer cell death.
  • Olaparib effectively decreased therapeutic resistance and cell migration in surviving cells.

Conclusions:

  • Genomic destabilization following DNA damage is a key driver of therapeutic resistance and metastasis.
  • The PARP inhibitor Olaparib mitigates resistance and metastatic potential by stabilizing the genome and enhancing cancer cell death.
  • Olaparib represents a promising therapeutic strategy to overcome treatment resistance and prevent metastasis in cancer patients.

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