pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry

被引：30

作者：

Jones, Gemma N. ^{[1
]}

Rooney, Claire ^{[1
]}

Griffin, Nicola ^{[2
]}

Roudier, Martine ^{[1
]}

Young, Lucy A. ^{[2
]}

Garcia-Trinidad, Antonio ^{[2
]}

Hughes, Gareth D. ^{[2
]}

Whiteaker, Jeffrey R. ^{[3
]}

Wilson, Zena ^{[2
]}

Odedra, Rajesh ^{[2
]}

Zhao, Lei ^{[3
]}

Ivey, Richard G. ^{[3
]}

Howat, William J. ^{[1
]}

Harrington, Elizabeth A. ^{[1
]}

Barrett, J. Carl ^{[1
]}

Ramos-Montoya, Antonio ^{[2
]}

Lau, Alan ^{[2
]}

Paulovich, Amanda G. ^{[3
]}

Cadogan, Elaine B. ^{[2
]}

Pierce, Andrew J. ^{[1
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Translat Sci, Oncol, Cambridge, England

[2] AstraZeneca, IMED Biotech Unit, Oncol Biosci, Cambridge, England

[3] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA

来源：

BRITISH JOURNAL OF CANCER | 2018年 / 119卷 / 10期

基金：

美国国家卫生研究院;

关键词：

PEPTIDE IMMUNOAFFINITY ENRICHMENT; DNA-DAMAGE RESPONSE; CELL LUNG-CANCER; ATAXIA-TELANGIECTASIA; DEPENDENT PHOSPHORYLATION; PROTEIN EXPRESSION; MRN COMPLEX; RAD50; TUMOR; QUANTIFICATION;

D O I：

10.1038/s41416-018-0286-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangtectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage. METHODS: We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue. RESULTS: We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34-72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors. CONCLUSION: Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.

引用

页码：1233 / 1243

页数：11

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