PARP inhibitors were recently approved for treatment of molecularly-defined subsets
of metastatic castrate-resistant prostate cancer (mCRPC) patients. Although the PARP
inhibitor olaparib was approved for use in patients with a mutation in one of fourteen
genes, the mutation frequency of the genes varies widely in mCRPC and the impact of
the less commonly altered genes on PARP inhibitor sensitivity is uncertain. We used
functional approaches to directly test the impact of PALB2 and BARD1 loss on homologous
recombination (HR) function and PARP inhibitor sensitivity in prostate cancer cell
lines. PALB2 or BARD1 loss led to decreased HR function as measured by loss of radiation-induced
Rad51 foci formation as well as decreased HR capacity in a cell-based reporter assay.
PALB2 or BARD1 loss also significantly increased sensitivity to the PARP inhibitors
olaparib and rucaparib across a panel of prostate cancer cell lines. These data support
PALB2 and BARD1 loss as markers of clinically relevant PARP inhibitor sensitivity
and highlight the potential to use functional approaches to complement and extend
findings from clinical trials of targeted agents.
