BibTex format
@article{McNeish:2021,
author = {McNeish, I},
journal = {NAR Cancer},
title = {Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During Development of PARP Inhibitor Resistance},
year = {2021}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian canceroften results from secondary mutations that restore expression of functional protein. RAD51C is aless commonly studied ovarian cancer susceptibility gene whose promoter is sometimesmethylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For thisstudy, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR genemutations but harbors RAD51C promoter methylation, was selected for PARPi resistance bycyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycleand grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profilingthroughout the course of resistance development showed widespread pathway level changes alongwith a marked increase in RAD51C mRNA, which reflected loss of RAD51C promotermethylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparibmonotherapy likewise indicated an association between loss of RAD51C methylation prior to onstudy biopsy and limited response. Interestingly, the PARPi resistant PH039 model remainedplatinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure canreverse RAD51C methylation and restore RAD51C expression, but also provide a model forstudying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.
AU - McNeish,I
PY - 2021///
TI - Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During Development of PARP Inhibitor Resistance
T2 - NAR Cancer
ER -