EGFR amplification induces increased DNA damage response and renders selective sensitivity to Talazoparib (PARP inhibitor) in glioblastoma

EGFR amplification induces increased DNA damage response and renders selective sensitivity to Talazoparib (PARP inhibitor) in glioblastoma:

Purpose: Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here we identified EGFR-amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for GBM patient population who will benefit from PARP inhibition therapy. Experimental Design: Selective sensitivity to PARP inhibitor talazoparib was screened and validated in two sets [test set (n=14) and validation set (n=13)] of well-characterized patient-derived glioma-sphere-forming cells (GSC). FISH was used to detect EGFR copy number. DNA damage response following talazoparib treatment was evaluated by H2AX and 53BP1 staining and neutral comet assay. PARP-DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using in-vivo glioma models. Results: EGFR-amplified GSCs showed remarkable sensitivity to talazoparib treatment. EGFR- amplification was associated with increased ROS and subsequent increased basal expression of DNA repair pathways to counter elevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, EGFR-amplified GSCs showed enhanced DNA damage and increased PARP-DNA trapping which augmented the cytotoxicity. EGFR-amplification associated selective sensitivity was further supported by the in vivo experimental results showing that talazoparib significantly suppressed tumor growth in EGFR-amplified subcutaneous models but not in non-amplified models. Conclusion: EGFR-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using EGFR amplification as a selection biomarker for the development of personalized therapy.