PLoS ONE (Jan 2023)

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

  • Mafuka Suzuki,
  • Haruka Fujimori,
  • Kakeru Wakatsuki,
  • Yuya Manaka,
  • Haruka Asai,
  • Mai Hyodo,
  • Yusuke Matsuno,
  • Rika Kusumoto-Matsuo,
  • Mitsunori Shiroishi,
  • Ken-Ichi Yoshioka

DOI
https://doi.org/10.1371/journal.pone.0281168
Journal volume & issue
Vol. 18, no. 1
p. e0281168

Abstract

Read online

Malignancy is often associated with therapeutic resistance and metastasis, usually arising after therapeutic treatment. These include radio- and chemo-therapies, which cause cancer cell death by inducing DNA double strand breaks (DSBs). However, it is still unclear how resistance to these DSBs is induced and whether it can be suppressed. Here, we show that DSBs induced by camptothecin (CPT) and radiation jeopardize genome stability in surviving cancer cells, ultimately leading to the development of resistance. Further, we show that cytosolic DNA, accumulating as a consequence of genomic destabilization, leads to increased cGAS/STING-pathway activation and, ultimately, increased cell migration, a precursor of metastasis. Interestingly, these genomic destabilization-associated phenotypes were suppressed by the PARP inhibitor Olaparib. Recognition of DSBs by Rad51 and genomic destabilization were largely reduced by Olaparib, while the DNA damage response and cancer cell death were effectively increased. Thus, Olaparib decreases the risk of therapeutic resistance and cell migration of cells that survive radio- and CPT-treatments.