Shaofang Wu

Fujian Medical University

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Dimpy Koul

The University of Texas MD Anderson Cancer Center

Siyuan Zheng

Fujian University of Technology

W.K. Alfred Yung

The University of Texas MD Anderson Cancer Center

Roel G.W. Verhaak

Jackson Laboratory

Shuzhen Wang

Beijing Chao-Yang Hospital

Emmanuel Martínez-Ledesma

Tecnológico de Monterrey

Jie Ding

German Cancer Research Center

Feng Gao

Tianjin University

Nghi Nguyen

The University of Texas Southwestern Medical Center

Stephan C. Clifford

Texas A&M University

Cooperative Institutions

The University of Texas MD Anderson Cancer Center

Ministry of Agriculture and Rural Affairs

Fujian Agriculture and Forestry University

University of California, San Francisco

European School of Oncology

Dana-Farber Cancer Institute

Center for Neuro-Oncology

Harvard University

Southern Medical University

Huazhong University of Science and Technology

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Supplementary Materials and Methods from 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 Martínez-Ledesma

Supplementary Materials and Methods

PARP inhibitor

10.1158/1078-0432.22478232.v1

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Data from 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 Martínez-Ledesma

<div>AbstractPurpose: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.</div>

PARP inhibitor

10.1158/1078-0432.c.6529896

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[Epidemiological characteristics of suicide death in registered population in Zhuhai].

PubMed (2007)

Deyun Li Qi Chen Liang Xiao-dong Shaofang Wu

To understand the epidemiological characteristics and the specific patterns of suicide death in Zhuhai population in order to provide decision-making evidence for suicide intervention.To describe epidemic properties of suicide death of registered population by using the data of Mortality Registration System from 2003 to 2005 in Zhuhai.From 2003 to 2005, the average death rate of suicide and the standard rate in registered population in Zhuhai were 6.43 and 6.61 per 100000, respectively. Suicide death was the second death cause following traffic accident. The standard rates for male, female, country and city population were 8.69, 4.68, 9.03 and 5.05 per 100000, respectively. The standard rate in male population was higher than that in female one (U = 3.47, P < 0.01), and the standard rate in the country was higher than that in the city (U = 3.45, P < 0.01). The average death rate of suicide increased with increasing age, especially in the male population over 60 years old. The main suicide ways included hanging oneself and taking poisons with their rates in all suicide deaths being up to 80%.The mean death rate of suicide in registered population in Zhuhai is lower than national average rate in China. The specific patterns of suicide death in Zhuhai population have suicide characteristics present both in China and in the foreign countries, that is, suicide death rate in the country is higher than in the city, and men are more likely to kill themselves than women, especially aged men.

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Supplemental Figure S6 from MSK1-Mediated β-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma

Shaofang Wu Shuzhen Wang Siyuan Zheng Roel G.W. Verhaak Dimpy Koul

β-catenin depletion decreased cell resistance to PI3K/mTOR inhibition

10.1158/1535-7163.22508736

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Supplemental Figure S4 from MSK1-Mediated β-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma

Shaofang Wu Shuzhen Wang Siyuan Zheng Roel G.W. Verhaak Dimpy Koul

Effect of MSK1 knock-down on cell growth.

10.1158/1535-7163.22508742

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Supplementary Data Figure S1 to S6, and Table S3 and S4. from Tie2–FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma

Xiaolong Li Emmanuel Martínez-Ledesma Chen Zhang Feng Gao Siyuan Zheng

This file contains supplementary Figure S1 to S6, and Table S3 and S4.

PLK1

10.1158/0008-5472.22421865.v1

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Data from Tie2–FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma

Xiaolong Li Emmanuel Martínez-Ledesma Chen Zhang Feng Gao Siyuan Zheng

<div>AbstractPI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere–forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor–induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy.Significance:These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.</div>

PLK1

Aurora kinase

Aurora B kinase

10.1158/0008-5472.c.6511056

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Table S2 from Tie2–FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma

Xiaolong Li Emmanuel Martínez-Ledesma Chen Zhang Feng Gao Siyuan Zheng

Compounds map of high-throughput drug screening

PLK1

Table (database)

10.1158/0008-5472.22421859