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

Shaofang Wu, Feng Gao, Siyuan Zheng, Chen Zhang, Emmanuel Martinez-Ledesma, Ravesanker Ezhilarasan, Jie Ding, Xiaolong Li, Ningping Feng, Asha Multani, Erik P. Sulman, Roel G. Verhaak, John F. de Groot, Tim P. Heffernan, W. K. Alfred Yung, Dimpy Koul

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1395-1407
Number of pages13
JournalClinical Cancer Research
Volume26
Issue number6
DOIs
StatePublished - Mar 15 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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