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

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 γH2AX 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 6 Pg. 1395-1407 (03 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31852834 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Phthalazines
• Poly(ADP-ribose) Polymerase Inhibitors
• talazoparib
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Brain Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• DNA Damage
• ErbB Receptors (genetics)
• Gene Amplification
• Glioblastoma (drug therapy, genetics, pathology)
• Humans
• Male
• Mice
• Mice, Nude
• Oxidative Stress
• Phthalazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Spheroids, Cellular
• Xenograft Model Antitumor Assays