TY - JOUR
T1 - EGFR amplification induces increased DNA damage response and renders selective sensitivity to talazoparib (PARP inhibitor) in glioblastoma
AU - Wu, Shaofang
AU - Gao, Feng
AU - Zheng, Siyuan
AU - Zhang, Chen
AU - Martinez-Ledesma, Juan Emmanuel
AU - Ezhilarasan, Ravesanker
AU - Ding, Jie
AU - Li, Xiaolong
AU - Feng, Ningping
AU - Multani, Asha
AU - Sulman, Erik Philip
AU - Verhaak, Roeland
AU - de Groot, John F.
AU - Heffernan, Tim P.
AU - Yung, W K Alfred
AU - Koul, Dimpy
N1 - Funding Information:
This study was funded by a National Brain Tumor Society (Defeat GBM) grant, National Foundation for Cancer Research (NFCR) to W.K.A. Yung, a SPORE grant (P50 CA127001 to F.F. Lang), and a Cancer Center Support Grant (CA016672). The authors would like to thank Verlene Henry and Caroline Carrillo for performing animal studies and Ann Sutton in Scientific Publications department for manuscript editing.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - 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 the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy. Experimental Design: Selective sensitivity to the 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 gH2AX 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 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, 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 nonamplified models. Conclusions: 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.
AB - 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 the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy. Experimental Design: Selective sensitivity to the 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 gH2AX 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 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, 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 nonamplified models. Conclusions: 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.
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U2 - 10.1158/1078-0432.CCR-19-2549
DO - 10.1158/1078-0432.CCR-19-2549
M3 - Article
C2 - 31852834
AN - SCOPUS:85081945872
SN - 1078-0432
VL - 26
SP - 1395
EP - 1407
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -