Data from PARP Inhibition Induces Enrichment of DNA Repair–Proficient CD133 and CD117 Positive Ovarian Cancer Stem Cells

Abstract

<div>Abstract<p>PARP inhibitors (PARPi) are FDA-approved monotherapy agents for the treatment of recurrent ovarian cancer in patients with and without a <i>BRCA</i> mutation. Despite promising response rates, not all patients derive benefit, and the majority develop resistance. PARPi treatment <i>in vitro</i> and <i>in vivo</i> induced an enrichment of CD133<sup>+</sup> and CD117<sup>+</sup> ovarian cancer stem cells (CSC). This effect was not affected by <i>BRCA</i> mutation status. In the CSC fractions, PARPi induced cell-cycle arrest in G<sub>2</sub>–M with a consequent accumulation of γH2AX, RAD51, and uniquely DMC1 foci. DNA damage and repair monitoring assays demonstrated that CSCs display more efficient DNA repair due, in part, to activation of embryonic repair mechanisms which involved the RAD51 homologue, DMC1 recombinase. Preserved and induced homologous repair (HR) could be a mechanism of an inherent resistance of CSCs to the synthetic lethality of PARPi that likely promotes disease recurrence.</p>Implications:<p>Treatment with PARPi fails to significantly affect ovarian cancer CSC populations, likely contributing to recurrent disease. Ovarian cancer CSCs stabilize genomic integrity after PARPi treatment, due to a more efficient inherent DNA repair capacity. PARPi-induced DMC1 recombinase and HR proficiency provide CSCs the opportunity to repair DNA damage more efficiently.</p><p><b>Visual Overview:</b> <a href="http://mcr.aacrjournals.org/content/molcanres/17/2/431/F1.large.jpg" target="_blank">http://mcr.aacrjournals.org/content/molcanres/17/2/431/F1.large.jpg</a>.</p></div>