<i>EGFR</i> Amplification Induces Increased DNA Damage Response and Renders Selective Sensitivity to Talazoparib (PARP Inhibitor) in Glioblastoma.

Abstract

Exploration of novel strategies to extend the benefit of PARP inhibitors beyond <i>BRCA</i>-mutant cancers is of great interest in personalized medicine. Here, we identified <i>EGFR</i> amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy. Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set (<i>n</i> = 14) and validation set (<i>n</i> = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect <i>EGFR</i> copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP-DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using <i>in vivo</i> glioma models. <i>EGFR</i>-amplified GSCs showed remarkable sensitivity to talazoparib treatment. <i>EGFR</i> amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, <i>EGFR</i>-amplified GSCs showed enhanced DNA damage and increased PARP-DNA trapping, which augmented the cytotoxicity. <i>EGFR</i> amplification-associated selective sensitivity was further supported by the <i>in vivo</i> experimental results showing that talazoparib significantly suppressed tumor growth in <i>EGFR</i>-amplified subcutaneous models but not in nonamplified models. <i>EGFR</i>-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using <i>EGFR</i> amplification as a selection biomarker for the development of personalized therapy.